U.S. patent application number 12/484552 was filed with the patent office on 2009-12-24 for novel heteroaryl carboxamide derivatives.
Invention is credited to Jean-Michel Adam, Johannes Aebi, Alferd Binggeli, Luke Green, Guido Hartmann, Hans P. Maerki, Patrizio Mattei, Fabienne Ricklin, Olivier Roche.
Application Number | 20090318467 12/484552 |
Document ID | / |
Family ID | 40887105 |
Filed Date | 2009-12-24 |
United States Patent
Application |
20090318467 |
Kind Code |
A1 |
Adam; Jean-Michel ; et
al. |
December 24, 2009 |
NOVEL HETEROARYL CARBOXAMIDE DERIVATIVES
Abstract
The invention is concerned with novel heteroaryl carboxamide
derivatives of formula (I), ##STR00001## wherein ##STR00002## m, X,
Y, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined in the
description and in the claims, as well as physiologically
acceptable salts thereof. These compounds are antagonists of CCR-2
receptor, CCR-5 receptor and/or CCR-3 receptor and can be used as
medicaments.
Inventors: |
Adam; Jean-Michel; (Rosenau,
FR) ; Aebi; Johannes; (Binningen, CH) ;
Binggeli; Alferd; (Binningen, CH) ; Green; Luke;
(Basel, CH) ; Hartmann; Guido; (Loerrach, DE)
; Maerki; Hans P.; (Basel, CH) ; Mattei;
Patrizio; (Riehen, CH) ; Ricklin; Fabienne;
(Hombourg, FR) ; Roche; Olivier; (Folgensbourg,
FR) |
Correspondence
Address: |
HOFFMANN-LA ROCHE INC.;PATENT LAW DEPARTMENT
340 KINGSLAND STREET
NUTLEY
NJ
07110
US
|
Family ID: |
40887105 |
Appl. No.: |
12/484552 |
Filed: |
June 15, 2009 |
Current U.S.
Class: |
514/253.09 ;
514/255.05; 514/256; 514/274; 514/275; 514/300; 514/316; 514/318;
544/310; 544/316; 544/333; 544/364; 544/405; 546/187; 546/194 |
Current CPC
Class: |
A61P 9/04 20180101; A61P
25/04 20180101; C07D 401/06 20130101; A61P 9/10 20180101; A61P 9/02
20180101; A61P 29/00 20180101; A61P 3/10 20180101; A61P 43/00
20180101; A61P 1/00 20180101; A61P 19/02 20180101; A61P 9/00
20180101; A61P 13/00 20180101; A61P 25/00 20180101; C07D 471/04
20130101; C07D 401/14 20130101; A61P 11/06 20180101; A61P 17/02
20180101; A61P 7/02 20180101 |
Class at
Publication: |
514/253.09 ;
546/194; 544/333; 544/405; 544/316; 544/310; 544/364; 546/187;
514/318; 514/256; 514/275; 514/274; 514/255.05; 514/316;
514/300 |
International
Class: |
A61K 31/4545 20060101
A61K031/4545; C07D 401/14 20060101 C07D401/14; A61K 31/506 20060101
A61K031/506; A61K 31/497 20060101 A61K031/497; A61K 31/496 20060101
A61K031/496; A61K 31/437 20060101 A61K031/437 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 18, 2008 |
EP |
08158499.7 |
Claims
1. A compound of formula (I): ##STR00107## or a tautomer, ester, or
pharmaceutically acceptable salt thereof, wherein: ##STR00108## is
a heterocyclyl substituted by --(R.sup.4).sub.m wherein m is 0, 1,
2, 3 or 4; and wherein said heterocyclyl is a non-aromatic
mono-cyclic radical of four to eight ring atoms, in which one or
two ring atoms are nitrogen atoms, with the remaining ring atoms
being carbon atoms; and wherein said structure: (1) does not
contain a nitrogen atom which is directly bonded to a heteroatom;
and (2) contains at least one nitrogen atom not directly bonded to
a carbonyl group; X--Y is selected from the group consisting of:
(1) N.dbd.C(NR.sup.10R.sup.11), (2) C(NR.sup.6R.sup.7).dbd.N, (3)
CR.sup.8.dbd.N, (4) C(O)--NR.sup.9, (5) N(O).dbd.CR.sup.12, (6)
N(R.sup.5)--C(O), (7) CR.sup.8.dbd.N(O), (8) N.dbd.N, ##STR00109##
R.sup.1 is selected from the group consisting of: (1) C.sub.1-6
alkyl, (2) C.sub.3-7 cycloalkyl, (3) C.sub.2-6 alkenyl, (4)
C.sub.2-6 alkynyl, (5) optionally substituted C.sub.3-7 cycloalkyl,
(6) optionally substituted C.sub.3-7 cycloalkyl C.sub.1-6 alkyl,
(7) C.sub.1-6 alkoxy, (8) halo C.sub.1-6 alkoxy, (9) halo C.sub.1-6
alkyl, (10) C.sub.3-7 cycloalkoxy, (11) heteroalkyl, (12)
heteroalkoxy, (13) halogen, (14) optionally substituted phenyl
which does not have nitro as a substituent, (15) optionally
substituted heteroaryl, and (16) optionally substituted
heterocyclyl; R.sup.2 is hydrogen, C.sub.1-6 alkyl, C.sub.2-6
alkynyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkyl, cyano or halogen;
R.sup.3is phenyl or heteroaryl wherein said heteroaryl is an
aromatic mono-cyclic radical of six ring atoms, in which one or two
ring atoms are nitrogen atoms with the remaining ring atoms being
carbon atoms, and wherein said phenyl or said heteroaryl are
substituted by one, two or three substituents independently
selected from the group consisting of C.sub.1-8 alkyl, halo
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, halogen
and cyano; R.sup.4 is: (a) attached to a ring carbon atom and
independently selected from the group consisting of: (1) hydrogen,
(2) C.sub.1-6 alkyl, (3) hydroxy C.sub.1-6 alkyl or halo C.sub.1-6
alkyl, (4) heteroalkyl, (5) C.sub.2-6 alkenyl, (6) C.sub.2-6
alkynyl, (7) hydroxy C.sub.3-6 alkenyl, (8) hydroxy C.sub.3-6
alkynyl, (9) C.sub.1-6 alkoxy C.sub.3-6 alkenyl, (10) C.sub.1-6
alkoxy C.sub.3-6 alkynyl, (11) hydroxy, (12) C.sub.1-6 alkoxy, (13)
halo C.sub.1-6 alkoxy, (14) heteroalkoxy, (15) halogen, (16) cyano,
(17) optionally substituted phenyl, (18) optionally substituted
C.sub.3-7 cycloalkyl, (19) optionally substituted C.sub.3-7
cycloalkyl C.sub.1-6 alkyl, (20) optionally substituted heteroaryl,
(21) optionally substituted heterocyclyl, (22) optionally
substituted phenyl-C.sub.1-6 alkyl, (23) optionally substituted
heteroaryl-C.sub.1-6 alkyl, (24) optionally substituted
heterocyclyl-C.sub.1-6 alkyl, (25) nitro, (26) carboxy, (27)
formyl, (28) acyl, (29) C.sub.1-6 alkoxycarbonyl, (30) carbamoyl,
(31) mono- or di-C.sub.1-6 alkyl substituted aminocarbonyl, (32)
C.sub.1-6 alkylthio, (33) C.sub.1-6 alkylsulfinyl, (34) C.sub.1-6
alkylsulfonyl, and (35) amino optionally substituted by one or two
substituents independently selected from the group consisting of
C.sub.1-6 alkyl, heteroalkyl, optionally substituted C.sub.3-7
cycloalkyl and optionally substituted heterocyclyl; or (b) attached
to a ring nitrogen atom and independently selected from the group
consisting of: (1) hydrogen, (2) C.sub.1-6 alkyl, (3) hydroxy
C.sub.1-6 alkyl or halo C.sub.1-6 alkyl, (4) heteroalkyl, (5)
C.sub.2-6 alkenyl, (6) C.sub.2-6 alkynyl, (7) hydroxy C.sub.3-6
alkenyl, (8) hydroxy C.sub.3-6 alkynyl, (9) C.sub.1-6 alkoxy
C.sub.3-6 alkenyl, (10) C.sub.1-6 alkoxy C.sub.3-6 alkynyl, (11)
optionally substituted C.sub.3-7 cycloalkyl, (12) optionally
substituted C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, (13) optionally
substituted heterocyclyl, and (14) optionally substituted
heterocyclyl C.sub.1-6 alkyl; R.sup.5is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, halo C.sub.1-6 alkyl, or heteroalkyl; R.sup.6 and
R.sup.10 are independently of each other selected from the group
consisting of: hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkanoyl,
C.sub.1-6 alkylsulfonyl, C.sub.3-7 cycloalkyl, optionally
substituted phenyl-C.sub.1-6 alkyl, optionally substituted
heteroaryl-C.sub.1-6 alkyl, and optionally substituted
heterocyclyl-C.sub.1-6 alkyl; R.sup.7 and R.sup.11 are
independently of each other selected from the group consisting of:
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, halo C.sub.1-6
alkyl, C.sub.1-6 alkanoyl, and heteroalkyl; R.sup.8 is selected
from the group consisting of: (1) hydrogen, (2) hydroxy, (3)
mercapto, (4) C.sub.1-6 alkyl, (5) C.sub.3-7 cycloalkyl, (6)
C.sub.2-6 alkenyl, (7) C.sub.2-6 alkynyl, (8) optionally
substituted C.sub.3-7 cycloalkyl, (9) optionally substituted
C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, (10) C.sub.1-6 alkoxy, (11)
C.sub.1-6 alkylthio, (12) halo C.sub.1-6 alkoxy, (13) halo
C.sub.1-6 alkyl, (14) C.sub.3-7 cycloalkoxy, (15) heteroalkyl, (16)
heteroalkoxy, (17) halogen, (18) cyano, (19) optionally substituted
phenyl, (20) optionally substituted heteroaryl, (21) optionally
substituted heterocyclyl, (22) optionally substituted phenyloxy,
(23) optionally substituted heteroaryloxy; (24) optionally
substituted phenylthio, (25) optionally substituted heteroarylthio;
(26) optionally substituted phenyl-C.sub.1-6 alkoxy, (27)
optionally substituted heteroaryl-C.sub.1-6 alkoxy, (28) C.sub.1-6
alkoxy-carbonyl, (29) carboxy, and (30) --CONR.sup.13R.sup.14;
R.sup.9 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, halo
C.sub.1-6 alkyl, heteroalkyl, optionally substituted heteroaryl,
optionally substituted phenyl-C.sub.1-6 alkyl, or optionally
substituted heteroaryl-C.sub.1-6 alkyl; R.sup.12 is hydrogen,
C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, heteroalkyl, optionally
substituted C.sub.3-7 cycloalkyl, optionally substituted C.sub.3-7
cycloalkyl C.sub.1-6 alkyl, optionally substituted phenyl,
optionally substituted heteroaryl, or optionally substituted
heterocyclyl; and R.sup.13 is hydrogen, C.sub.1-6 alkyl,
heteroalkyl, optionally substituted C.sub.3-7 cycloalkyl,
optionally substituted heterocyclyl, optionally substituted aryl,
or optionally substituted heteroaryl; and R.sup.14 is hydrogen,
C.sub.1-6 alkyl or heteroalkyl; or alternatively, R.sup.13 and
R.sup.14 taken together with the nitrogen atom to which they are
attached, form an optionally substituted heterocyclyl ring; except
that
[4-isobutyl-6-(2-isopropyl-phenyl)-pyridazin-3-yl]-(3-isopropyl
piperazin-1-yl)-methanone and
(3-benzyl-piperazin-1-yl)-[4-isobutyl-6-(2-isopropyl-phenyl)-pyridazin-3--
yl]-methanone are excluded from the genus of formula (I).
2. A compound of claim 1, wherein X--Y is C(NR.sup.6R.sup.7).dbd.N,
CR.sup.8.dbd.N or C(O)--NR.sup.9.
3. A compound of claim 1, wherein X--Y is C(NH.sub.2).dbd.N,
CH.dbd.N, C(Cl).dbd.N, C(O)--NH, C(pyridinyl)=N, C(triazolyl)=N,
C(NH((CH.sub.2).sub.2OH)).dbd.N, C(NH.sub.2-pyrimidinyl)=N,
C(CH.sub.2OH).dbd.N, C(pyrazinyl)=N, C(C(O)NH(pyridinyl))=N, or
C(O)--N(CH.sub.3).
4. A compound of claim 1, wherein X--Y is C(NH.sub.2).dbd.N,
C(NH.sub.2-pyrimidinyl)=N, C(pyrazinyl)=N, C(triazolyl)=N or
C(O)--NH.
5. A compound of claim 1, wherein ##STR00110## is piperidin-1-yl or
[1,4]diazepan-1-yl.
6. A compound of claim 1, wherein ##STR00111## is
piperidin-1-yl.
7. A compound of claim 1, wherein m is 1.
8. A compound of claim 1, wherein R.sup.4 is optionally substituted
heterocyclyl or heteroalkyl.
9. A compound of claim 1, wherein R.sup.4 is hydroxy C.sub.1-6
alkyl, optionally substituted pyrrolidin-1-yl, or optionally
substituted piperidin-1-yl.
10. A compound of claim 1, wherein R.sup.4 is piperidin-1-yl or
pyrrolidin-1-yl, wherein said piperidin-1-yl or pyrrolidin-1-yl is
optionally substituted by hydroxyl C.sub.1-6 alkyl or hydroxy.
11. A compound of claim 1, wherein R.sup.4 is pyrrolidin-1-yl,
2-hydroxymethyl-pyrrolidin-1-yl or 4-hydroxy-piperidin-1-yl.
12. A compound of claim 1, wherein: ##STR00112## is
4-pyrrolidin-1-yl-piperidin-1-yl,
4-(2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl, or
4-hydroxy-[1,4']bipiperidinyl-1'-yl.
13. A compound of claim 1, wherein R.sup.1 is C.sub.1-6 alkyl,
halogen, or optionally substituted phenyl, and R.sup.2 is hydrogen
or halogen.
14. A compound of claim 1, wherein R.sup.1 is C.sub.1-6 alkyl and
R.sup.2 is hydrogen.
15. A compound of claim 1, wherein R.sup.1 is methyl and R.sup.2 is
hydrogen.
16. A compound of claim 1, wherein R.sup.3 is phenyl or pyridyl,
wherein said phenyl or pyridyl is optionally substituted by one or
two substituents independently selected from the group consisting
of trifluoromethyl and trifluoromethoxy.
17. A compound of claim 1, wherein R.sup.3 is 3-trifluoromethyl
phenyl.
18. A compound of claim 1, wherein R.sup.13 is hydrogen, C.sub.1-6
alkyl, heteroalkyl, pyridinyl, optionally substituted piperidinyl,
optionally substituted piperazinyl and R.sup.14 is hydrogen.
19. A compound of claim 1, wherein R.sup.13 is hydrogen, methyl,
hydroxyethyl, 1-carboxylic acid-t-butyl ester-piperidin-4-yl,
pyridin-3yl, 1-carboxylic acid-t-butyl ester-piperazin-4-yl,
piperidin-4-yl or piperazin-4-yl and R.sup.14 is hydrogen.
20. A compound of claim 1, selected from the group consisting of:
[3-Methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-p-
iperidin-1-yl)-methanone,
[6-Chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone,
[4-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[3-methyl-5-(3-t-
rifluoromethyl-phenyl)-pyridin-2-yl]-methanone,
[6-Hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone,
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-1H-pyridin-2-one,
[6-Amino-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone,
[5-Methyl-3-(3-trifluoromethyl-phenyl)-[2,3']bipyridinyl-6-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone,
[3-Chloro-6-hydroxy-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone,
5-Chloro-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-1H-pyridin-2-one,
[3-Methyl-6-[1,2,4]triazol-1-yl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl-
]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
[6-(2-Hydroxy-ethylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-
-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
[5-(2-Fluoro-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone,
[3-Methyl-6-(1H-[1,2,3]triazol-4-yl)-5-(3-trifluoromethyl-phenyl)-pyridin-
-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
[5-(2-Methoxy-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone,
[6-(2-Amino-pyrimidin-5-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-
-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
[6-Hydroxymethyl-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-p-
yrrolidin-1-yl-piperidin-1-yl)-methanone,
[3-Methyl-6-pyrazin-2-yl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-py-
rrolidin-1-yl-piperidin-1-yl)-methanone,
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid pyridin-3-ylamide, and
1,5-Dimethyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluorome-
thyl-phenyl)-1H-pyridin-2-one.
21. A process for manufacturing a compound of formula (I):
##STR00113## comprising a step of reacting a compound of formula
(II): ##STR00114## with a compound of formula (III): ##STR00115##
wherein ##STR00116## m, R.sup.1, R.sup.2, R.sup.3, R.sup.4, X--Y
are as defined in claim 1.
22. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable excipient.
Description
PRIORITY TO RELATED APPLICATION(S)
[0001] This application claims the benefit of European Patent
Application No. 08158499.7, filed Jun. 18, 2008, which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Chemokines are a family of small, secreted proinflammatory
cytokines functioning as chemoattractants for leukocytes. They
promote trafficking of leukocytes from vascular beds into
surrounding tissues in response to inflammatory signals. Chemotaxis
starts upon chemokine binding to receptors (GPCRs) by initiating
signaling pathways involving increased Ca-flux, inhibition of cAMP
production, rearrangements of the cytoskeleton, activation of
integrins and of cell motility processes and an increase in the
expression of adhesion proteins.
[0003] Proinflammatory chemokines are considered to be involved in
the development of atherosclerosis and other important diseases
with inflammatory components like rheumatoid arthritis, asthma,
multiple sclerosis, transplant rejection and ischemia reperfusion
injury with specific prominent effects in nephropathy and
peripheral vascular diseases. Monocyte Chemotactic Protein 1 is
considered to be the major stimulated chemokine mediating
inflammatory processes in these diseases through the CCR2 receptor
on monocytes and on some T lymphocytes. In addition MCP-1/CCR2 are
in discussion to be related to the progression of the metabolic
syndrome to more severe stages of obese and diabetic diseases.
[0004] CCR2 has also been linked to HIV infection, and consequently
the course of autoimmune diseases, through its heterodimerization
with CCR5 which has a role as coreceptor for viral entry into host
cells.
[0005] Thus, CCR2 can be a target of a new medicine for treatment
of peripheral vascular diseases, and more specifically for
treatment of patients with critical limb ischemia. Furthermore,
study results and experiences from the development of a new CCR2
medicine for this indication may facilitate a follow-up development
for treatment of atherosclerosis. There is a large body of
information from animal models of MCP-1 and CCR2 ko mice in wt or
apoE-/- or LDL-R-/- backgrounds showing that the MCP-1/CCR2 pathway
is essential for monocyte/macrophage recruitment, and also for
intimal hyperplasia and the formation and stability of
atherosclerotic lesions. In addition, numerous reports describe
involvement of the MCP-1/CCR2 pathway in man post injury and in
various inflammatory processes, including such in vascular
beds.
[0006] The present invention provides the novel compounds of
formula (I) which are CCR2 receptor antagonists, with some
antagonist activity also at CCR-3 and CCR-5.
SUMMARY OF THE INVENTION
[0007] The invention is concerned with novel heteroaryl carboxamide
derivatives of formula (I),
##STR00003##
or tautomers, prodrugs, esters, or pharmaceutically acceptable
salts thereof, wherein:
##STR00004##
is a heterocyclyl substituted by --(R.sup.4).sub.m wherein m is 0,
1, 2, 3 or 4; and wherein said heterocyclyl is a non-aromatic
mono-cyclic radical of four to eight ring atoms, in which one or
two ring atoms are nitrogen atoms, with the remaining ring atoms
being carbon atoms; and wherein said heterocyclyl substituted by
--(R.sup.4).sub.m: (1) does not contain a nitrogen atom which is
directly bonded to a heteroatom; and (2) contains at least one
nitrogen atom not directly bonded to a carbonyl group; [0008] X--Y
is selected from the group consisting of:
[0009] (1) N.dbd.C(NR.sup.10R.sup.11),
[0010] (2) C(NR.sup.6R.sup.7).dbd.N,
[0011] (3) CR.sup.8.dbd.N,
[0012] (4) C(O)--NR.sup.9,
[0013] (5) N(O).dbd.CR.sup.12,
[0014] (6) N(R.sup.5)--C(O),
[0015] (7) CR.sup.8.dbd.N(O),
[0016] (8) N.dbd.N,
##STR00005## [0017] R.sup.1 is selected from the group consisting
of: (1) C.sub.1-6 alkyl, (2) C.sub.3-7 cycloalkyl, (3) C.sub.2-6
alkenyl, (4) C.sub.2-6 alkynyl, (5) optionally substituted
C.sub.3-7 cycloalkyl, (6) optionally substituted C.sub.3-7
cycloalkyl C.sub.1-6 alkyl, (7) C.sub.1-6 alkoxy, (8) halo
C.sub.1-6 alkoxy, (9) halo C.sub.1-6 alkyl, (10) C.sub.3-7
cycloalkoxy, (11) heteroalkyl, (12) heteroalkoxy, (13) halogen,
(14) optionally substituted phenyl which does not have nitro as a
substituent, (15) optionally substituted heteroaryl, and (16)
optionally substituted heterocyclyl; [0018] R.sup.2 is hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, halo
C.sub.1-6 alkyl, cyano or halogen; [0019] R.sup.3 is phenyl or
heteroaryl wherein said heteroaryl is an aromatic mono-cyclic
radical of six ring atoms, in which one or two ring atoms are
nitrogen atoms with the remaining ring atoms being carbon atoms,
and wherein said phenyl or said heteroaryl are substituted by one,
two or three substituents independently selected from the group
consisting of C.sub.1-8 alkyl, halo C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halo C.sub.1-6 alkoxy, halogen and cyano; [0020] R.sup.4
is: (a) attached to a ring carbon atom and independently selected
from the group consisting of: (1) hydrogen, (2) C.sub.1-6 alkyl,
(3) hydroxy C.sub.1-6 alkyl or halo C.sub.1-6 alkyl, (4)
heteroalkyl, (5) C.sub.2-6 alkenyl, (6) C.sub.2-6 alkynyl, (7)
hydroxy C.sub.3-6 alkenyl, (8) hydroxy C.sub.3-6 alkynyl, (9)
C.sub.1-6 alkoxy C.sub.3-6 alkenyl, (10) C.sub.1-6 alkoxy C.sub.3-6
alkynyl, (11) hydroxy, (12) C.sub.1-6 alkoxy, (13) halo C.sub.1-6
alkoxy, (14) heteroalkoxy, (15) halogen, (16) cyano, (17)
optionally substituted phenyl, (18) optionally substituted
C.sub.3-7 cycloalkyl, (19) optionally substituted C.sub.3-7
cycloalkyl C.sub.1-6 alkyl, (20) optionally substituted heteroaryl,
(21) optionally substituted heterocyclyl, (22) optionally
substituted phenyl-C.sub.1-6 alkyl, (23) optionally substituted
heteroaryl-C.sub.1-6 alkyl, (24) optionally substituted
heterocyclyl-C.sub.1-6 alkyl, (25) nitro, (26) carboxy, (27)
formyl, (28) acyl, (29) C.sub.1-6 alkoxycarbonyl, (30) carbamoyl,
(31) mono- or di-C.sub.1-6 alkyl substituted aminocarbonyl, (32)
C.sub.1-6 alkylthio, (33) C.sub.1-6 alkylsulfinyl, (34) C.sub.1-6
alkylsulfonyl, and (35) amino optionally substituted by one or two
substituents independently selected from the group consisting of
C.sub.1-6 alkyl, heteroalkyl, optionally substituted C.sub.3-7
cycloalkyl and optionally substituted heterocyclyl; or [0021] (b)
attached to a ring nitrogen atom and independently selected from
the group consisting of: (1) hydrogen, (2) C.sub.1-6 alkyl, (3)
hydroxy C.sub.1-6 alkyl or halo C.sub.1-6 alkyl, (4) heteroalkyl,
(5) C.sub.2-6 alkenyl, (6) C.sub.2-6 alkynyl, (7) hydroxy C.sub.3-6
alkenyl, (8) hydroxy C.sub.3-6 alkynyl, (9) C.sub.1-6 alkoxy
C.sub.3-6 alkenyl, (10) C.sub.1-6 alkoxy C.sub.3-6 alkynyl, (11)
optionally substituted C.sub.3-7 cycloalkyl, (12) optionally
substituted C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, (13) optionally
substituted heterocyclyl, and (14) optionally substituted
heterocyclyl C.sub.1-6 alkyl; [0022] R.sup.5is C.sub.1-6 alkyl,
C.sub.3-7 cycloalkyl, halo C.sub.1-6 alkyl, or heteroalkyl; [0023]
R.sup.6 and R.sup.10 are independently of each other selected from
the group consisting of: hydrogen, C.sub.1-6 alkyl, C.sub.1-6
alkanoyl, C.sub.1-6 alkylsulfonyl, C.sub.3-7 cycloalkyl, optionally
substituted phenyl-C.sub.1-6 alkyl, optionally substituted
heteroaryl-C.sub.1-6 alkyl, and optionally substituted
heterocyclyl-C.sub.1-6 alkyl; [0024] R.sup.7 and R.sup.11 are
independently of each other selected from the group consisting of:
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, halo C.sub.1-6
alkyl, C.sub.1-6 alkanoyl, and heteroalkyl; [0025] R.sup.8 is
selected from the group consisting of: (1) hydrogen, (2) hydroxy,
(3) mercapto, (4) C.sub.1-6 alkyl, (5) C.sub.3-7 cycloalkyl, (6)
C.sub.2-6 alkenyl, (7) C.sub.2-6 alkynyl, (8) optionally
substituted C.sub.3-7 cycloalkyl, (9) optionally substituted
C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, (10) C.sub.1-6 alkoxy, (11)
C.sub.1-6 alkylthio, (12) halo C.sub.1-6 alkoxy, (13) halo
C.sub.1-6 alkyl, (14) C.sub.3-7 cycloalkoxy, (15) heteroalkyl, (16)
heteroalkoxy, (17) halogen, (18) cyano, (19) optionally substituted
phenyl, (20) optionally substituted heteroaryl, (21) optionally
substituted heterocyclyl, (22) optionally substituted phenyloxy,
(23) optionally substituted heteroaryloxy; (24) optionally
substituted phenylthio, (25) optionally substituted heteroarylthio;
(26) optionally substituted phenyl-C.sub.1-6 alkoxy, (27)
optionally substituted heteroaryl-C.sub.1-6 alkoxy, (28) C.sub.1-6
alkoxy-carbonyl, (29) carboxy, and (30) --CONR.sup.13R.sup.14;
[0026] R.sup.9 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
halo C.sub.1-6 alkyl, heteroalkyl, optionally substituted
heteroaryl, optionally substituted phenyl-C.sub.1-6 alkyl, or
optionally substituted heteroaryl-C.sub.1-6 alkyl; [0027] R.sup.12
is hydrogen, C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, heteroalkyl,
optionally substituted C.sub.3-7 cycloalkyl, optionally substituted
C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, optionally substituted
phenyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl; and [0028] R.sup.13 is hydrogen,
C.sub.1-6 alkyl, heteroalkyl, optionally substituted C.sub.3-7
cycloalkyl, optionally substituted heterocyclyl, optionally
substituted aryl, or optionally substituted heteroaryl; and [0029]
R.sup.14 is hydrogen, C.sub.1-6 alkyl or heteroalkyl; or
alternatively, R.sup.13 and R.sup.14 taken together with the
nitrogen atom to which they are attached, form an optionally
substituted heterocyclyl ring; [0030] except that
[4-isobutyl-6-(2-isopropyl-phenyl)-pyridazin-3-yl]-(3-isopropyl
piperazin-1-yl)-methanone and
(3-benzyl-piperazin-1-yl)-[4-isobutyl-6-(2-isopropyl-phenyl)-pyridazin-3--
yl]-methanone are excluded from the genus of formula (I).
[0031] Further, the invention is concerned with a process for the
manufacture of the above compounds, pharmaceutical compositions
which contain such compounds, and the use of these compounds for
the production of pharmaceutical compositions.
[0032] The compounds of formula (I) are CCR2 receptor (Chemokine
Receptor 2/Monocyte Chemotactic Protein 1 Receptor) antagonists and
also CCR-5 receptor (Chemokine Receptor 5) and/or CCR-3 receptor
(Chemokine Receptor 3) antagonists and thus may be useful in
treating diseases and disorders associated with these
receptors.
DETAILED DESCRIPTION OF THE INVENTION
[0033] Unless otherwise indicated, the following definitions are
set forth to illustrate and define the meaning and scope of the
various terms used to describe the invention herein.
[0034] The term "heteroatom" means a nitrogen atom, an oxygen atom
or a sulphur atom.
[0035] The term "halogen" or "halo" refers to fluoro, chloro, bromo
or iodo. Preferred "halogen" groups are fluoro and chloro.
[0036] Unless otherwise indicated, the term "hydrogen" or "hydro"
refers to the moiety of a hydrogen atom (--H) and not H.sub.2.
[0037] The term "C.sub.1-6 alkyl", alone or in combination with
other groups, means a branched or straight-chain monovalent alkyl
radical, having one to six carbon atoms. This term is further
exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl,
n-butyl, s-butyl, t-butyl. C.sub.1-4 alkyl or C.sub.1-3 alkyl is
more preferred.
[0038] The term "hydroxy C.sub.1-6 alkyl" means a C.sub.1-6 alkyl
substituted by one or more hydroxy group(s).
[0039] The term "halo C.sub.1-6 alkyl" means a C.sub.1-6 alkyl
substituted by one or more of the same or different halogen atoms.
Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl,
1-iodomethyl, difluoromethyl, trifluoromethyl, trichloromethyl,
tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl,
1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl,
2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or
2,2,2-trifluoroethyl. In certain preferred embodiments the "halo
C.sub.1-6 alkyl" is a chloro- or fluoro-C.sub.1-6 alkyl. The most
preferred "halo C.sub.1-6 alkyl" is trifluoromethyl.
[0040] The term "C.sub.1-6 alkylene", alone or in combination with
other groups, means a branched or straight-chain saturated divalent
hydrocarbon radical of one to six carbon atoms, such as methylene,
ethylene, tetramethylethylene.
[0041] The term "C.sub.3-7 cycloalkyl", alone or in combination
with other groups, means a saturated monovalent mono-cyclic
hydrocarbon radical of three to seven ring carbons, e.g.,
cyclopropyl, cyclobutyl, cyclohexyl.
[0042] The term "C.sub.1-6 alkoxy", alone or in combination with
other groups, means the group R'--O--, wherein R' is a C.sub.1-6
alkyl.
[0043] The term "C.sub.1-6 alkoxy-carbonyl" refers to the group
R.sup.a1--C(O)--, wherein R.sup.a1 is C.sub.1-6 alkoxy as defined
above.
[0044] The term "halo C.sub.1-6 alkoxy", alone or in combination
with other groups, means a C.sub.1-6 alkoxy substituted by one or
more halogens. In certain preferred embodiments the halo of the
halo C.sub.1-6 alkoxy is substituted by one or three halogens.
[0045] The term "C.sub.2-6 alkenyl", alone or in combination with
other groups, means a straight-chain or branched hydrocarbon
residue comprising a carbon-carbon double bond, having two to six
carbon atoms. This term is further exemplified by such radicals as
ethenyl, 2-propenyl.
[0046] The term "hydroxy C.sub.3-6 alkenyl" means a C.sub.3-6
alkenyl substituted by one or more hydroxy groups. In certain
preferred embodiments the C.sub.3-6 alkenyl is substituted by one
or two hydroxy groups.
[0047] The term "C.sub.1-6 alkoxy C.sub.3-6 alkenyl" means a
C.sub.3-6 alkenyl substituted by one or more C.sub.1-6 alkoxy
groups. In certain preferred embodiments the C.sub.3-6 alkenyl is
substituted by one or two C.sub.1-6 alkoxy groups.
[0048] The term "C.sub.2-6-alkynyl", alone or in combination with
other groups, means a straight-chain or branched hydrocarbon
residue comprising a carbon-carbon triple bond, having two to six
carbon atoms. This term is further exemplified by such radicals as
ethynyl, 2-propynyl.
[0049] The term "hydroxy C.sub.3-6 alkynyl" means a C.sub.3-6
alkynyl substituted by one or more hydroxy groups. In certain
preferred embodiments, the C.sub.3-6 alkynyl is substituted by one
or two hydroxy groups.
[0050] The term "C.sub.1-6 alkoxy C.sub.3-6 alkenyl" means a
C.sub.3-6 alkynyl substituted by one or more C.sub.1-6 alkoxy
groups. In certain preferred embodiments, the C.sub.3-6 alkynyl is
substituted by one or two C.sub.1-6 alkoxy groups.
[0051] The term "acyl" or "C.sub.1-6alkanoyl" means R--C(O)--, in
which R is C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl or C.sub.3-7 cycloalkyl C.sub.1-6 alkyl.
[0052] The term "heteroalkyl" means a C.sub.1-6 alkyl substituted
by one or more substituents selected independently from the group
consisting of nitro, hydroxy, cyano, C.sub.1-6 alkoxy, formyl,
acyl, carboxy, C.sub.1-6 alkylthio, C.sub.1-6 alkyl sulfinyl,
C.sub.1-6 alkyl sulfonyl, carbamoyl, amino and mono- or
di-C.sub.1-6 alkyl substituted amino.
[0053] The term "heteroalkoxy" means C.sub.1-6 alkoxy substituted
by one or more substituents selected independently from the group
consisting of nitro, hydroxy, cyano, C.sub.1-6 alkoxy, formyl,
acyl, carboxy, C.sub.1-6 alkylthio, C.sub.1-6 alkyl sulfinyl,
C.sub.1-6 alkyl sulfonyl, carbamoyl, amino and mono- or
di-C.sub.1-6 alkyl substituted amino.
[0054] The term "heterocyclyl" means non-aromatic mono-cyclic
radicals of four to seven ring atoms, in which one to three ring
atoms are heteroatoms independently selected from N, O and
S(O).sub.n (where n is an integer from 0 to 2), the remaining ring
atoms being C. In particular, the term "heterocyclyl" includes, but
is not limited to, tetrahydrofuranyl, tetrahydropyranyl,
piperidino, N-methylpiperidin-3-yl, piperazino,
N-methylpyrrolidin-3-yl, 3-pyrrolidino, morpholino, thiomorpholino,
thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,
4-(1,1-dioxo-tetrahydro-2H-thiopyranyl), pyrrolinyl, imidazolinyl,
N-methanesulfonyl-piperidin-4-yl, and the derivatives thereof. The
most preferred heterocyclyls are piperazinyl, pyrolindinyl or
piperidinyl.
[0055] The term "heteroaryl" means an aromatic mono-cyclic radical
of 5 or 6 ring atoms, having one to three ring heteroatoms
independently selected from N, O, and S, with the remaining ring
atoms being C. More specifically the term "heteroaryl" includes,
but is not limited to, pyridinyl, furanyl, thienyl, thiazolyl,
isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl,
pyrimidinyl, pyrazolyl, pyrazinyl, pyrimidinyl, benzofuranyl,
tetrahydrobenzofuranyl, isobenzofuranyl, benzothiazolyl,
benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl,
benzoxazolyl, quinolyl, tetrahydroquinolinyl, isoquinolyl,
benzimidazolyl, benzisoxazolyl or benzothienyl,
imidazo[1,2-a]-pyridinyl, imidazo[2,1-b]thiazolyl, and the
derivatives thereof. The most preferred heteroaryls are pyridinyl,
pyrimidinyl, triazolyl, pyrazolyl, pyrazinyl.
[0056] The term "optionally substituted C.sub.3-7 cycloalkyl" means
a C.sub.3-7 cycloalkyl optionally substituted by one to three
substituents independently selected from the group consisting of
C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, heteroalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, hydroxy C.sub.3-6 alkenyl, hydroxy
C.sub.3-6 alkynyl, C.sub.1-6 alkoxy C.sub.3-6 alkenyl, C.sub.1-6
alkoxy C.sub.3-6 alkynyl, hydroxy, C.sub.1-6 alkoxy, halo C.sub.1-6
alkoxy, heteroalkoxy, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl
C.sub.1-6 alkyl, halogen, cyano, nitro, amino, mono- or
di-C.sub.1-6 alkyl substituted amino, carboxy, formyl, acyl,
C.sub.1-6 alkoxycarbonyl, carbamoyl, mono- or di-C.sub.1-6 alkyl
substituted aminocarbonyl, C.sub.1-6 alkylthio, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl and acylamino.
[0057] The term "optionally substituted C.sub.3-7 cycloalkyl
--C.sub.1-6 alkyl" means the group R.sup.8ae-R.sup.8af--, wherein
R.sup.8ae and R.sup.8af are, respectively, "optionally substituted
C.sub.3-7 cycloalkyl" and "C.sub.1-6 alkyl" as defined above.
[0058] The term "optionally substituted phenyl" means a phenyl
optionally substituted by one to three substituents independently
selected from the group consisting of C.sub.1-6 alkyl, halo
C.sub.1-6 alkyl, heteroalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
hydroxy C.sub.3-6 alkenyl, hydroxy C.sub.3-6 alkynyl, C.sub.1-6
alkoxy C.sub.3-6 alkenyl, C.sub.1-6 alkoxy C.sub.3-6 alkynyl,
hydroxy, C.sub.1-6 alkoxy, halo C.sub.1-6 alkoxy, heteroalkoxy,
C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl C.sub.1-6 alkyl,
halogen, cyano, nitro, amino, mono- or di-C.sub.1-6 alkyl
substituted amino, carboxy, formyl, acyl, C.sub.1-6 alkoxycarbonyl,
carbamoyl, mono- or di-C.sub.1-6 alkyl substituted aminocarbonyl,
C.sub.1-6 alkylthio, C.sub.1-6 alkylsulfinyl, C.sub.1-6
alkylsulfonyl and acylamino.
[0059] The term "optionally substituted phenyloxy" means the group
R.sup.8a--O--, wherein R.sup.8a is "optionally substituted phenyl"
as defined above.
[0060] The term "optionally substituted phenylthio" means the group
R.sup.8a'--S--, wherein R.sup.8a' is "optionally substituted
phenyl" as defined above.
[0061] The term "optionally substituted phenyl-C.sub.1-6 alkoxy"
means the group R.sup.8aa--R.sup.8ab--, wherein R.sup.8aa and
R.sup.8ab are, respectively, "optionally substituted phenyl" and
"C.sub.1-6 alkoxy" as defined above.
[0062] The term "optionally substituted phenyl-C.sub.1-6 alkyl"
means the group R.sup.8ac-R.sup.8ad--, wherein R.sup.8ac and
R.sup.8ad are, respectively, "optionally substituted phenyl" and
"C.sub.1-6 alkyl" as defined above.
[0063] The term "optionally substituted heterocyclyl" means a
heterocyclyl optionally substituted by one to three substituents
independently selected from the group consisting of C.sub.1-6
alkyl, halo C.sub.1-6 alkyl, heteroalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, hydroxy C.sub.3-6 alkenyl, hydroxy C.sub.3-6
alkynyl, C.sub.1-6 alkoxy C.sub.3-6 alkenyl, C.sub.1-6 alkoxy
C.sub.3-6 alkynyl, hydroxy, C.sub.1-6 alkoxy, halo C.sub.1-6
alkoxy, heteroalkoxy, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl
C.sub.1-6 alkyl, halogen, cyano, nitro, amino, mono- or
di-C.sub.1-6 alkyl substituted amino, carboxy, formyl, acyl,
C.sub.1-6 alkoxycarbonyl, carbamoyl, mono- or di-C.sub.1-6 alkyl
substituted aminocarbonyl, C.sub.1-6 alkylthio, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl and acylamino.
[0064] The term "optionally substituted heterocyclyl-C.sub.1-6
alkyl" means the group R.sup.8be-R.sup.8bf--, wherein R.sup.8be and
R.sup.bf are, respectively, "optionally substituted heterocyclyl"
and "C.sub.1-6 alkyl" as defined above.
[0065] The term "optionally substituted heteroaryl" means a
heteroaryl optionally substituted by one to three substituents
independently selected from the group consisting of C.sub.1-6
alkyl, halo C.sub.1-6 alkyl, heteroalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, hydroxy C.sub.3-6 alkenyl, hydroxy C.sub.3-6
alkynyl, C.sub.1-6 alkoxy C.sub.3-6 alkenyl, C.sub.1-6 alkoxy
C.sub.3-6 alkynyl, hydroxy, C.sub.1-6 alkoxy, halo C.sub.1-6
alkoxy, heteroalkoxy, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkyl
C.sub.1-6 alkyl, halogen, cyano, nitro, amino, mono- or
di-C.sub.1-6 alkyl substituted amino, carboxy, formyl, acyl,
C.sub.1-6 alkoxycarbonyl, carbamoyl, mono- or di-C.sub.1-6 alkyl
substituted aminocarbonyl, C.sub.1-6 alkylthio, C.sub.1-6
alkylsulfinyl, C.sub.1-6 alkylsulfonyl and acylamimo.
[0066] The term "optionally substituted heteroaryloxy" means
R.sup.8b--O--, wherein R.sup.8b is "optionally substituted
heteroaryl" as defined above.
[0067] The term "optionally substituted heteroarylthio" means
R.sup.8b'--S--, wherein R.sup.8b' is "optionally substituted
heteroaryl" as defined above.
[0068] The term "optionally substituted heteroaryl-C.sub.1-6
alkoxy" means the group R.sup.8ba-R.sup.8bb--, wherein R.sup.8ba
and R.sup.8bb are, respectively, "optionally substituted
heteroaryl" and "C.sub.1-6 alkoxy" as defined above.
[0069] The term "optionally substituted heteroaryl-C.sub.1-6 alkyl"
means the group R.sup.8bc-R.sup.bd--, wherein R.sup.8bc and
R.sup.8bd are, respectively, "optionally substituted heteroaryl"
and "C.sub.1-6 alkyl" as defined above.
[0070] The terms, "C.sub.1-6 alkylsulfonyl", "C.sub.1-6
alkylsulfinyl" and "C.sub.1-6 alkylthio", alone or combination with
other groups, means C.sub.1-6 alkyl-SO.sub.2--, C.sub.1-6
alkyl-SO-- and C.sub.1-6 alkyl-S--, respectively.
[0071] Unless otherwise indicated, in reference to a particular
group or molecule, the term "substituted" refers to the fact that
at least one of the hydrogen atoms of that group or molecule is
replaced by some other substituent.
[0072] Unless otherwise indicated, the terms "optional" or
"optionally" means that the subsequently described event or
circumstance may but need not occur, and that the description
includes instances where the event or circumstance occurs and
instances in which it does not. For example, an "aryl group
optionally substituted with an alkyl group" means that the alkyl
may but need not be present, and the description includes
situations where the aryl group is substituted with an alkyl group
and situations where the aryl group is not substituted with the
alkyl group.
[0073] The term "a therapeutically effective amount" of a compound
means an amount of compound that is effective to prevent, alleviate
or ameliorate symptoms of disease or prolong the survival of the
subject being treated. Determination of a therapeutically effective
amount is within the skill in the art. The therapeutically
effective amount or dosage of a compound according to this
invention can vary within wide limits and may be determined in a
manner known in the art. Such dosage will be adjusted to the
individual requirements in each particular case including the
specific compound(s) being administered, the route of
administration, the condition being treated, as well as the patient
being treated. In general, in the case of oral or parenteral
administration to adult humans weighing approximately 70 Kg, a
daily dosage of about 0.1 mg to about 5,000 mg, preferably from
about 0.1 mg to about 1,000 mg, more preferably from about 0.5 to
500 mg, and more preferably from about 1 mg to 100 mg, should be
appropriate, although the upper limit may be exceeded when
indicated. The daily dosage can be administered as a single dose or
in divided doses, or for parenteral administration, it may be given
as continuous infusion.
[0074] The term "pharmaceutically acceptable carrier" is intended
to include any and all material compatible with pharmaceutical
administration including solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents, and other materials and compounds compatible with
pharmaceutical administration. Except insofar as any conventional
media or agent is incompatible with the active compound, use
thereof in the compositions of the invention are contemplated.
Supplementary active compounds can also be incorporated into the
compositions.
[0075] Preferred radicals for the chemical groups whose definitions
are given above are those specifically exemplified in Examples.
[0076] Compounds of formula (I) can form pharmaceutically
acceptable acid addition salts. Examples of such pharmaceutically
acceptable salts are salts of compounds of formula (I) with
physiologically compatible mineral acids, such as hydrochloric
acid, hydrobromic acid, sulphuric acid, sulphurous acid or
phosphoric acid; or with organic acids, such as methanesulphonic
acid, p-toluenesulphonic acid, acetic acid, lactic acid,
trifluoroacetic acid, citric acid, fumaric acid, maleic acid,
tartaric acid, succinic acid or salicylic acid. The term
"pharmaceutically acceptable salts" refers to such salts. Compounds
of formula (I) may also be present in the form of pharmaceutically
acceptable esters (i.e., the methyl and ethyl esters of the acids
of formula I to be used as prodrugs).
[0077] Unless otherwise indicated, the term "a compound of the
formula" or "a compound of formula" or "compounds of the formula"
or "compounds of formula" refers to any compound selected from the
genus of compounds as defined by the formula (including any
pharmaceutically acceptable salt of any such compound).
[0078] "Pharmaceutically acceptable excipient" means an excipient
that is useful in preparing a pharmaceutical composition that is
generally safe, non-toxic and neither biologically nor otherwise
undesirable, and includes excipient that is acceptable for
veterinary use as well as human pharmaceutical use. A
"pharmaceutically acceptable excipient" as used in the
specification and claims includes both one and more than one such
excipient.
[0079] Compounds that have the same molecular formula but differ in
the nature or sequence of bonding of their atoms or the arrangement
of their atoms in space are termed "isomers." Isomers that differ
in the arrangement of their atoms in space are termed
"stereoisomers". Stereoisomers that are not mirror images of one
another are termed "diastereomers" and those that are
non-superimposable mirror images of each other are termed
"enantiomers". When a compound has an asymmetric center, for
example, if a carbon atom is bonded to four different groups, a
pair of enantiomers is possible. An enantiomer can be characterized
by the absolute configuration of its asymmetric center and is
described by the R- and S-sequencing rules of Cahn, Ingold and
Prelog, or by the manner in which the molecule rotates the plane of
polarized light and designated as dextrorotatory or levorotatory
(i.e., as (+) or (-)-isomers respectively). A chiral compound can
exist as either individual enantiomer or as a mixture thereof. A
mixture containing equal proportions of the enantiomers is called a
"racemic mixture".
[0080] The compounds of formula (I) can possess one or more
asymmetric centers. Unless indicated otherwise, the description or
naming of a particular compound in the specification and claims is
intended to include both individual enantiomers and mixtures,
racemic or otherwise, thereof, as well as individual epimers and
mixture thereof. The methods for the determination of
stereochemistry and the separation of stereoisomers are well-known
in the art (see discussion in Chapter 4 of "Advanced Organic
Chemistry", 4th edition J. March, John Wiley and Sons, New York,
1992).
[0081] In addition, certain compounds of formula (I) may exist in
more than one tautomeric form. The present invention encompasses
all such tautomers, as well as mixtures thereof.
[0082] In detail, the present invention relates to the compounds of
formula (I):
##STR00006##
or tautomers, prodrugs, esters or pharmaceutically acceptable salts
thereof, wherein:
##STR00007##
is a heterocyclyl substituted by --(R.sup.4).sub.m wherein m is 0,
1, 2, 3 or 4; and wherein said heterocyclyl is a non-aromatic
mono-cyclic radical of four to eight ring atoms, in which one or
two ring atoms are nitrogen atoms, with the remaining ring atoms
being carbon atoms; and wherein said structure: (1) does not
contain a nitrogen atom which is directly bonded to a heteroatom;
and (2) contains at least one nitrogen atom not directly bonded to
a carbonyl group; [0083] X--Y is selected from the group consisting
of:
[0084] (1) N.dbd.C(NR.sup.10R.sup.11),
[0085] (2) C(NR.sup.6R.sup.7).dbd.N,
[0086] (3) CR.sup.8.dbd.N,
[0087] (4) C(O)--NR.sup.9,
[0088] (5) N(O).dbd.CR.sup.12,
[0089] (6) N(R.sup.5)--C(O),
[0090] (7) CR.sup.8.dbd.N(O),
[0091] (8) N.dbd.N,
##STR00008## [0092] R.sup.1 is selected from the group consisting
of: (1) C.sub.1-6 alkyl, (2) C.sub.3-7 cycloalkyl, (3) C.sub.2-6
alkenyl, (4) C.sub.2-6 alkynyl, (5) optionally substituted
C.sub.3-7 cycloalkyl, (6) optionally substituted C.sub.3-7
cycloalkyl C.sub.1-6 alkyl, (7) C.sub.1-6 alkoxy, (8) halo
C.sub.1-6 alkoxy, (9) halo C.sub.1-6 alkyl, (10) C.sub.3-7
cycloalkoxy, (11) heteroalkyl, (12) heteroalkoxy, (13) halogen,
(14) optionally substituted phenyl which does not have nitro as a
substituent, (15) optionally substituted heteroaryl, and (16)
optionally substituted heterocyclyl; [0093] R.sup.2 is hydrogen,
C.sub.1-6 alkyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, halo
C.sub.1-6 alkyl, cyano or halogen; [0094] R.sup.3is phenyl or
heteroaryl wherein said heteroaryl is an aromatic mono-cyclic
radical of six ring atoms, in which one or two ring atoms are
nitrogen atoms with the remaining ring atoms being carbon atoms,
and wherein said phenyl or said heteroaryl are substituted by one,
two or three substituents independently selected from the group
consisting of C.sub.1-8 alkyl, halo C.sub.1-6 alkyl, C.sub.1-6
alkoxy, halo C.sub.1-6 alkoxy, halogen and cyano; [0095] R.sup.4
is: (a) attached to a ring carbon atom and independently selected
from the group consisting of: (1) hydrogen, (2) C.sub.1-6 alkyl,
(3) hydroxy C.sub.1-6 alkyl or halo C.sub.1-6 alkyl, (4)
heteroalkyl, (5) C.sub.2-6 alkenyl, (6) C.sub.2-6 alkynyl, (7)
hydroxy C.sub.3-6 alkenyl, (8) hydroxy C.sub.3-6 alkynyl, (9)
C.sub.1-6 alkoxy C.sub.3-6 alkenyl, (10) C.sub.1-6 alkoxy C.sub.3-6
alkynyl, (11) hydroxy, (12) C.sub.1-6 alkoxy, (13) halo C.sub.1-6
alkoxy, (14) heteroalkoxy, (15) halogen, (16) cyano, (17)
optionally substituted phenyl, (18) optionally substituted
C.sub.3-7 cycloalkyl, (19) optionally substituted C.sub.3-7
cycloalkyl C.sub.1-6 alkyl, (20) optionally substituted heteroaryl,
(21) optionally substituted heterocyclyl, (22) optionally
substituted phenyl-C.sub.1-6 alkyl, (23) optionally substituted
heteroaryl-C.sub.1-6 alkyl, (24) optionally substituted
heterocyclyl-C.sub.1-6 alkyl, (25) nitro, (26) carboxy, (27)
formyl, (28) acyl, (29) C.sub.1-6 alkoxycarbonyl, (30) carbamoyl,
(31) mono- or di-C.sub.1-6 alkyl substituted aminocarbonyl, (32)
C.sub.1-6 alkylthio, (33) C.sub.1-6 alkylsulfinyl, (34) C.sub.1-6
alkylsulfonyl, and (35) amino optionally substituted by one or two
substituents independently selected from the group consisting of
C.sub.1-6 alkyl, heteroalkyl, optionally substituted C.sub.3-7
cycloalkyl and optionally substituted heterocyclyl; or [0096] (b)
attached to a ring nitrogen atom and independently selected from
the group consisting of: (1) hydrogen, (2) C.sub.1-6 alkyl, (3)
hydroxy C.sub.1-6 alkyl or halo C.sub.1-6 alkyl, (4) heteroalkyl,
(5) C.sub.2-6 alkenyl, (6) C.sub.2-6 alkynyl, (7) hydroxy C.sub.3-6
alkenyl, (8) hydroxy C.sub.3-6 alkynyl, (9) C.sub.1-6 alkoxy
C.sub.3-6 alkenyl, (10) C.sub.1-6 alkoxy C.sub.3-6 alkynyl, (11)
optionally substituted C.sub.3-7 cycloalkyl, (12) optionally
substituted C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, (13) optionally
substituted heterocyclyl, and (14) optionally substituted
heterocyclyl C.sub.1-6 alkyl; [0097] R.sup.5is C.sub.1-6 alkyl,
C.sub.3-7 cycloalkyl, halo C.sub.1-6 alkyl, or heteroalkyl; [0098]
R.sup.6 and R.sup.10 are independently of each other selected from
the group consisting of: hydrogen, C.sub.1-6 alkyl, C.sub.1-6
alkanoyl, C.sub.1-6 alkylsulfonyl, C.sub.3-7 cycloalkyl, optionally
substituted phenyl-C.sub.1-6 alkyl, optionally substituted
heteroaryl-C.sub.1-6 alkyl, and optionally substituted
heterocyclyl-C.sub.1-6 alkyl; [0099] R.sup.7 and R.sup.11 are
independently of each other selected from the group consisting of:
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, halo C.sub.1-6
alkyl, C.sub.1-6 alkanoyl, and heteroalkyl; [0100] R.sup.8 is
selected from the group consisting of: (1) hydrogen, (2) hydroxy,
(3) mercapto, (4) C.sub.1-6 alkyl, (5) C.sub.3-7 cycloalkyl, (6)
C.sub.2-6 alkenyl, (7) C.sub.2-6 alkynyl, (8) optionally
substituted C.sub.3-7 cycloalkyl, (9) optionally substituted
C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, (10) C.sub.1-6 alkoxy, (11)
C.sub.1-6 alkylthio, (12) halo C.sub.1-6 alkoxy, (13) halo
C.sub.1-6 alkyl, (14) C.sub.3-7 cycloalkoxy, (15) heteroalkyl, (16)
heteroalkoxy, (17) halogen, (18) cyano, (19) optionally substituted
phenyl, (20) optionally substituted heteroaryl, (21) optionally
substituted heterocyclyl, (22) optionally substituted phenyloxy,
(23) optionally substituted heteroaryloxy; (24) optionally
substituted phenylthio, (25) optionally substituted heteroarylthio;
(26) optionally substituted phenyl-C.sub.1-6 alkoxy, (27)
optionally substituted heteroaryl-C.sub.1-6 alkoxy, (28) C.sub.1-6
alkoxy-carbonyl, (29) carboxy, and (30) --CONR.sup.13R.sup.14;
[0101] R.sup.9 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
halo C.sub.1-6 alkyl, heteroalkyl, optionally substituted
heteroaryl, optionally substituted phenyl-C.sub.1-6 alkyl, or
optionally substituted heteroaryl-C.sub.1-6 alkyl; [0102] R.sup.12
is hydrogen, C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, heteroalkyl,
optionally substituted C.sub.3-7 cycloalkyl, optionally substituted
C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, optionally substituted
phenyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl; and [0103] R.sup.13 is hydrogen,
C.sub.1-6 alkyl, heteroalkyl, optionally substituted C.sub.3-7
cycloalkyl, optionally substituted heterocyclyl, optionally
substituted aryl, or optionally substituted heteroaryl; and [0104]
R.sup.14 is hydrogen, C.sub.1-6 alkyl or heteroalkyl; or
alternatively, R.sup.13 and R.sup.14 taken together with the
nitrogen atom to which they are attached, form an optionally
substituted heterocyclyl ring; [0105] except that
[4-isobutyl-6-(2-isopropyl-phenyl)-pyridazin-3-yl]-(3-isopropyl
piperazin-1-yl)-methanone and
(3-benzyl-piperazin-1-yl)-[4-isobutyl-6-(2-isopropyl-phenyl)-pyridazin-3--
yl]-methanone are excluded from the genus of formula (I).
[0106] In another embodiment the invention provides compounds of
formula (I):
##STR00009##
or tautomers, progdrugs, esters, or pharmaceutically acceptable
salts thereof, wherein:
##STR00010##
is a heterocyclyl substituted by --(R.sup.4).sub.m wherein m is 0,
1, 2, 3 or 4; and wherein said heterocyclyl is a non-aromatic
mono-cyclic radical of four to eight ring atoms, in which one or
two ring atoms are nitrogen atoms, with the remaining ring atoms
being carbon atoms; and wherein said structure: (1) does not
contain a nitrogen atom which is directly bonded to a heteroatom;
and (2) contains at least one nitrogen atom not directly bonded to
a carbonyl group; [0107] X--Y is selected from the group consisting
of:
[0108] (1) N.dbd.C(NR.sup.10R.sup.11),
[0109] (2) C(NR.sup.6R.sup.7).dbd.N,
[0110] (3) CR.sup.8.dbd.N,
[0111] (4) C(O)--NR.sup.9,
[0112] (5) N(O).dbd.CR.sup.12,
[0113] (6) N(R.sup.5)--C(O),
[0114] (7) CR.sup.8.dbd.N(O), and
[0115] (8) N.dbd.N; [0116] R.sup.1 is selected from the group
consisting of: (1) C.sub.1-6 alkyl, (2) C.sub.3-7 cycloalkyl, (3)
C.sub.2-6 alkenyl, (4) C.sub.2-6 alkynyl, (5) optionally
substituted C.sub.3-7 cycloalkyl, (6) optionally substituted
C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, (7) C.sub.1-6 alkoxy, (8)
halo C.sub.1-6 alkoxy, (9) halo C.sub.1-6 alkyl, (10) C.sub.3-7
cycloalkoxy, (11) heteroalkyl, (12) heteroalkoxy, (13) halogen,
(14) optionally substituted phenyl which does not have nitro as a
substituent, (15) optionally substituted heteroaryl, and (16)
optionally substituted heterocyclyl; [0117] R.sup.2 is hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo C.sub.1-6 alkyl, or
halogen; [0118] R.sup.3is phenyl or heteroaryl wherein said
heteroaryl is an aromatic mono-cyclic radical of six ring atoms, in
which one or two ring atoms are nitrogen atoms with the remaining
ring atoms being carbon atoms, and wherein said phenyl or said
heteroaryl are substituted by one, two or three substituents
independently selected from the group consisting of C.sub.1-8
alkyl, halo C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo C.sub.1-6
alkoxy, halogen and cyano; [0119] R.sup.4 is: (a) attached to a
ring carbon atom and independently selected from the group
consisting of: (1) hydrogen, (2) C.sub.1-6 alkyl, (3) hydroxy
C.sub.1-6 alkyl or halo C.sub.1-6 alkyl, (4) heteroalkyl, (5)
C.sub.2-6 alkenyl, (6) C.sub.2-6 alkynyl, (7) hydroxy C.sub.3-6
alkenyl, (8) hydroxy C.sub.3-6 alkynyl, (9) C.sub.1-6 alkoxy
C.sub.3-6 alkenyl, (10) C.sub.1-6 alkoxy C.sub.3-6 alkynyl, (11)
hydroxy, (12) C.sub.1-6 alkoxy, (13) halo C.sub.1-6 alkoxy, (14)
heteroalkoxy, (15) halogen, (16) cyano, (17) optionally substituted
phenyl, (18) optionally substituted C.sub.3-7 cycloalkyl, (19)
optionally substituted C.sub.3-7 cycloalkyl C.sub.1-6 alkyl, (20)
optionally substituted heteroaryl, (21) optionally substituted
heterocyclyl, (22) optionally substituted phenyl-C.sub.1-6 alkyl,
(23) optionally substituted heteroaryl-C.sub.1-6 alkyl, (24)
optionally substituted heterocyclyl-C.sub.1-6 alkyl, (25) nitro,
(26) carboxy, (27) formyl, (28) acyl, (29) C.sub.1-6
alkoxycarbonyl, (30) carbamoyl, (31) mono- or di-C.sub.1-6 alkyl
substituted aminocarbonyl, (32) C.sub.1-6 alkylthio, (33) C.sub.1-6
alkylsulfinyl, (34) C.sub.1-6 alkylsulfonyl, and (35) amino
optionally substituted by one or two substituents independently
selected from the group consisting of C.sub.1-6 alkyl, heteroalkyl,
optionally substituted C.sub.3-7 cycloalkyl and optionally
substituted heterocyclyl; or [0120] (b) attached to a ring nitrogen
atom and independently selected from the group consisting of: (1)
hydrogen, (2) C.sub.1-6 alkyl, (3) hydroxy C.sub.1-6 alkyl or halo
C.sub.1-6 alkyl, (4) heteroalkyl, (5) C.sub.2-6 alkenyl, (6)
C.sub.2-6 alkynyl, (7) hydroxy C.sub.3-6 alkenyl, (8) hydroxy
C.sub.3-6 alkynyl, (9) C.sub.1-6 alkoxy C.sub.3-6 alkenyl, (10)
C.sub.1-6 alkoxy C.sub.3-6 alkynyl, (11) optionally substituted
C.sub.3-7 cycloalkyl, (12) optionally substituted C.sub.3-7
cycloalkyl C.sub.1-6 alkyl, (13) optionally substituted
heterocyclyl, and (14) optionally substituted heterocyclyl
C.sub.1-6 alkyl; [0121] R.sup.5 is C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, halo C.sub.1-6 alkyl, or heteroalkyl; [0122] R.sup.6
and R.sup.10 are independently of each other selected from the
group consisting of: hydrogen, C.sub.1-6 alkyl, C.sub.1-6 alkanoyl,
C.sub.1-6 alkylsulfonyl, C.sub.3-7 cycloalkyl, optionally
substituted phenyl-C.sub.1-6 alkyl, optionally substituted
heteroaryl-C.sub.1-6 alkyl, and optionally substituted
heterocyclyl-C.sub.1-6 alkyl; [0123] R.sup.7 and R.sup.11 are
independently of each other selected from the group consisting of:
hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, halo C.sub.1-6
alkyl, C.sub.1-6 alkanoyl, and heteroalkyl; [0124] R.sup.8 is
selected from the group consisting of: (1) hydrogen, (2) hydroxy,
(3) C.sub.1-6 alkyl, (4) C.sub.3-7 cycloalkyl, (5) C.sub.2-6
alkenyl, (6) C.sub.2-6 alkynyl, (7) optionally substituted
C.sub.3-7 cycloalkyl, (8) optionally substituted C.sub.3-7
cycloalkyl C.sub.1-6 alkyl, (9) C.sub.1-6 alkoxy, (10) halo
C.sub.1-6 alkoxy, (11) halo C.sub.1-6 alkyl, (12) C.sub.3-7
cycloalkoxy, (13) heteroalkyl, (14) heteroalkoxy, (15) halogen,
(16) optionally substituted phenyl, (17) optionally substituted
heteroaryl, and (18) optionally substituted heterocyclyl; [0125]
R.sup.9 is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, halo
C.sub.1-6 alkyl, and heteroalkyl; and [0126] R.sup.12 is hydrogen,
C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, heteroalkyl, optionally
substituted C.sub.3-7 cycloalkyl, optionally substituted C.sub.3-7
cycloalkyl C.sub.1-6 alkyl, optionally substituted phenyl,
optionally substituted heteroaryl, or optionally substituted
heterocyclyl; [0127] except that
[4-isobutyl-6-(2-isopropyl-phenyl)-pyridazin-3-yl]-(3-isopropyl
piperazin-1-yl)-methanone and
(3-benzyl-piperazin-1-yl)-[4-isobutyl-6-(2-isopropyl-phenyl)-pyridazin-3--
yl]-methanone are excluded from the genus of formula (I).
[0128] While the broadest definition of this invention is described
before, certain compounds of formula (I) are preferred. [0129] i)
In the compounds of formula (I), X--Y is C(NR.sup.6R.sup.7).dbd.N,
CR.sup.8.dbd.N or C(O)--NR.sup.9, preferably X--Y is
C(NH.sub.2).dbd.N, CH.dbd.N, C(Cl).dbd.N, C(O)--NH, C(pyridinyl)=N,
C(triazolyl)=N, C(NH((CH.sub.2).sub.2OH)).dbd.N,
C(NH.sub.2-pyrimidinyl).dbd.N, C(CH.sub.2OH).dbd.N, C(pyrazinyl)=N,
C(C(O)NH(pyridinyl))=N or C(O)--N(CH.sub.3), more preferably
C(NH.sub.2).dbd.N, C(NH.sub.2-pyrimidinyl)=N, C(pyrazinyl)=N,
CH.dbd.N, C(triazolyl)=N C(Cl).dbd.N or C(O)--NH, and most
preferably X--Y is C(NH.sub.2).dbd.N, C(NH.sub.2-pyrimidinyl)=N,
C(pyrazinyl)=N, C(triazolyl)=N or C(O)--NH. [0130] ii) In the
compounds of formula (I), R.sup.10 and R.sup.11 are preferably
hydrogen, when X--Y is N.dbd.C(NR.sup.10R.sup.11). [0131] iii) In
the compounds of formula (I), R.sup.6 is preferably hydrogen,
C.sub.1-6 alkanoyl, optionally substituted phenyl-C.sub.1-6 alkyl
or C.sub.1-6 alkylsulfonyl and R.sup.7 is hydrogen, C.sub.1-6
alkanoyl, amino-C.sub.1-6alkyl- or hydroxy-C.sub.1-6alkyl-, when
X--Y is C(NR.sup.6R.sup.7).dbd.N. More preferably R.sup.6 and
R.sup.7 are hydrogen or hydrogen and hydroxyethyl, respectively.
Most preferably R.sup.6 and R.sup.7 are hydrogen. [0132] iv) In the
compounds of formula (I), R.sup.8 is preferably hydrogen, halogen,
mercapto, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, heteroalkyl,
heteroalkoxy, cyano, optionally substituted pyridinyl, optionally
substituted pyrimdinyl, optionally substituted triazolyl,
optionally substituted pyrazolyl, optionally substituted pyrazinyl,
C.sub.1-6 alkoxy-carbonyl, carboxy or --CONR.sup.13R.sup.14,
wherein R.sup.13 and R.sup.14 are defined herein, more preferebly,
R.sup.8 is hydrogen, halogen or C.sub.1-6 alkoxy and R.sup.8 is
most preferably chlorine, pyridin-3-yl, [1,2,4]triazol-1-yl,
2-amino-pyrimidin-5-yl or pyrazin-2-yl when X--Y is CR.sup.8.dbd.N.
[0133] v) In the compounds of formula (I), R.sup.5 is preferably
C.sub.1-6 alkyl and R.sup.5 is more preferably methyl, when X--Y is
N(R.sup.5)--C(O). [0134] vi) In the compounds of formula (I),
R.sup.8 is preferably hydrogen, when X--Y is CR.sup.8.dbd.N(O).
[0135] vii) In the compounds of formula (I),
##STR00011##
[0135] is preferably piperidin-1-yl or [1,4]diazepan-1-yl, and more
preferably piperidin-1-yl. [0136] viii) In the compounds of formula
(I), m is preferably 1. [0137] ix) In the compounds of formula (I),
R.sup.4 is preferably optionally substituted heterocyclyl or
heteroalkyl, more preferably, R.sup.4 is hydroxy C.sub.1-6 alkyl,
optionally substituted pyrrolidin-1-yl or optionally substituted
piperidin-1-yl, and more preferably R.sup.4 is piperidin-1-yl or
pyrrolidin-1-yl, said piperidin-1-yl and pyrrolidin-1-yl being
optionally substituted by hydroxyl C.sub.1-6 alkyl or hydroxy.
R.sup.4 is especially preferably pyrrolidin-1-yl,
2-hydroxymethyl-pyrrolidin-1-yl or 4-hydroxy-piperidin-1-yl. [0138]
x) In the compounds of formula (I), R.sup.4 is pyrrolidin-1-yl,
2-hydroxymethyl-pyrrolidin-1-yl or 4-hydroxy-piperidin-1-yl. [0139]
xi) In the compounds of formula (I),
##STR00012##
[0139] is preferably 4-pyrrolidin-1-yl-piperidin-1-yl,
4-(2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl or
4-hydroxy-[1,4']bipiperidinyl-1'-yl. [0140] xii) In the compounds
of formula (I), R.sup.1 is C.sub.1-6 alkyl, halogen or optionally
substituted phenyl, preferably C.sub.1-6 alkyl, especially methyl.
In the compounds of formula (I), R.sup.2 is preferably hydrogen or
halogen, especially hydrogen. [0141] xiii) In the compounds of
formula (I), R.sup.3 is preferably phenyl or pyridyl, said phenyl
and pyridyl being optionally substituted by one or two substituents
independently selected from the group consisting of trifluoromethyl
and trifluoromethoxy. R.sup.3 is more preferably 3-trifluoromethyl
phenyl. [0142] xiv) in the compounds of formula (I) R.sup.13 is
preferably hydrogen, C.sub.1-6 alkyl, heteroalkyl, pyridinyl,
optionally substituted piperidinyl, optionally substituted
piperazinyl and more preferably R.sup.13 is hydrogen, methyl,
hydroxyethyl, 1-carboxylic acid-t-butyl ester-piperidin-4-yl,
pyridin-3yl, 1-carboxylic acid-t-butyl ester-piperazin-4-yl,
piperidin-4-yl or piperazin-4-yl, and most preferably R.sup.13 is
pyridin-3yl. In the compounds of formula (I), R.sup.14 is
preferably hydrogen. [0143] xv) A preferred compound of the
invention is a compound of formula (I), which is
[3-Methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-p-
iperidin-1-yl)-methanone,
[6-Chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone,
[4-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[3-methyl-5-(3-t-
rifluoromethyl-phenyl)-pyridin-2-yl]-methanone,
[6-Hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone or its tautomeric form
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-1H-pyridin-2-one,
[6-Amino-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone,
[5-Methyl-3-(3-trifluoromethyl-phenyl)-[2,3']bipyridinyl-6-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone,
[3-Chloro-6-hydroxy-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone or its tautomeric form
5-Chloro-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-1H-pyridin-2-one,
[3-Methyl-6-[1,2,4]triazol-1-yl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl-
]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
[6-(2-Hydroxy-ethylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-
-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
[5-(2-Fluoro-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone,
[3-Methyl-6-(1H-[1,2,3]triazol-4-yl)-5-(3-trifluoromethyl-phenyl)-pyridin-
-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
[5-(2-Methoxy-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone,
[6-(2-Amino-pyrimidin-5-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-
-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone,
[6-Hydroxymethyl-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-p-
yrrolidin-1-yl-piperidin-1-yl)-methanone,
[3-Methyl-6-pyrazin-2-yl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-py-
rrolidin-1-yl-piperidin-1-yl)-methanone,
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid pyridin-3-ylamide, or
1,5-Dimethyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluorome-
thyl-phenyl)-1H-pyridin-2-one.
[0144] In a further embodiment the invention provides a compound of
formula (I):
##STR00013##
or tautomers, progdrugs, esters, or pharmaceutically acceptable
salts thereof, wherein: [0145] X--Y is N.dbd.C(NR.sup.10R.sup.11),
C(NR.sup.6R.sup.7).dbd.N, CR.sup.8.dbd.N, C(O)--NR.sup.9,
N(R.sup.5)--C(O), CR.sup.8.dbd.N(O) or
[0145] ##STR00014## [0146] R.sup.1 is C.sub.1-6 alkyl, halogen or
optionally substituted phenyl, provided that optionally substituted
phenyl does not have nitro as a substituent; [0147] R.sup.2 is
hydrogen or halogen; [0148] R.sup.3 is phenyl substituted by one,
two or three substituents independently selected from the group
consisting of halo C.sub.1-6 alkyl, C.sub.1-6 alkoxy and halogen;
[0149] R.sup.4 is, when attached to a ring carbon atom, optionally
substituted azetidinyl, pyrrolidinyl, piperidinyl or azepanyl, most
preferably pyrrolidinyl; [0150] m is 1;
##STR00015##
[0150] is piperidinyl; [0151] R.sup.5 is C.sub.1-6 alkyl; [0152]
R.sup.6 and R.sup.10 are independently hydrogen, C.sub.1-6
alkanoyl, C.sub.1-6 alkylsulfonyl or optionally substituted
phenyl-C.sub.1-6 alkyl; [0153] R.sup.7 and R.sup.11 are
independently hydrogen, C.sub.1-6 alkanoyl or heteroalkyl; [0154]
R.sup.8 is hydrogen, mercapto, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy,
heteroalkyl, heteroalkoxy, halogen, cyano, optionally substituted
pyridinyl, optionally substituted pyrimdinyl, optionally
substituted triazolyl, optionally substituted pyrazolyl, optionally
substituted pyrazinyl, C.sub.1-6 alkoxy-carbonyl, carboxy or
--CONR.sup.13R.sup.14; [0155] R.sup.9 is hydrogen or C.sub.1-6
alkyl; and [0156] R.sup.13 is hydrogen, C.sub.1-6 alkyl,
hydroxyethyl, pyridinyl, optionally substituted piperidinyl,
optionally substituted piperazinyl; and R.sup.14 is hydrogen; or
R.sup.13 and R.sup.14 taken together with the nitrogen atom to
which they are attached, form piperazinyl.
General Synthetic Procedures
[0157] The compounds of formula (I) can be manufactured by methods
known in the art, by the methods given below, by the methods given
in the examples or by analogous methods. Appropriate reaction
conditions for the individual reaction steps are known to a person
skilled in the art. Starting materials are either commercially
available or are known or can be prepared by methods given below or
by methods described in the examples, or by methods known in the
art.
[0158] The syntheses of the compounds of general formula (I) are
described in Scheme 1 to Scheme 9.
##STR00016## ##STR00017##
[0159] (In Scheme 1,
##STR00018##
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8 and m
are defined as described before. R.sup.a is C.sub.1-6 alkyl.
R.sup.i is independently hydrogen or C.sub.1-6 alkyl, or both
R.sup.is together form a C.sub.1-6 alkylene group. R.sup.ii is
C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
heteroalkyl, said heteroalkyl optionally carrying a protective
function which can be removed subsequently, aryl, heteroaryl,
optionally substituted phenyl-C.sub.1-6 alkyl or optionally
substituted heteroaryl-C.sub.1-6 alkyl. R.sup.iii is C.sub.1-6
alkyl and X is halogen or trifluoromethylsulfonyloxy)
[0160] Halo pyridine esters 1 are commercially available, are known
or can be prepared by methods known in the art. Suzuki couplings,
the reaction with aryl or heteroaryl boronic acids or esters 2 in
the presence of a catalyst, such as
tetrakis-(triphenylphosphine)-palladium or
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
optionally in the form of a dichloromethane complex (1:1), and in
the presence of a base, such as potassium phosphate, or sodium or
potassium carbonate, in a solvent, such as toluene, dioxane,
tetrahydrofuran or N,N-dimethylformamide and in an inert atmosphere
such as argon or nitrogen, in a temperature range preferably
between room temperature and about 130.degree. C. can be applied to
transform halo pyridine esters 1 into aryl pyridine esters 3 (step
a). Oxidation of aryl pyridine esters 3 with meta-chloro-perbenzoic
acid preferably in dichloromethane at room temperature or with
hydrogen peroxide urea adduct and trifluoroacetic anhydride in
dichloromethane or acetonitrile between 0.degree. C. and room
temperature gives N-oxides 4 (step b). Treatment of N-oxides 4 with
phosphorus oxychloride preferably between about 50.degree. C. and
about 100.degree. C. gives chloro-pyridine esters 5 and/or 6,
provided R.sup.8 and/or R.sup.2 are hydrogen (step c). Chloro
pyridine esters 5 and 6 can be saponified, e.g. by treatment with
lithium or potassium hydroxide in a solvent like tetrahydrofuran,
ethanol or 2-ethoxy-ethanol and mixtures thereof in a temperature
range between room temperature and about 150.degree. C. to give
acids 7 and 8 (step d). Aryl pyridine acids 7 and 8 can then be
coupled with secondary amines (III) to aryl pyridine amides 9 and
10 i) by transformation of the aryl pyridine acids 7 and 8 into the
corresponding acid chlorides, preferably by reaction with oxalyl
chloride and a catalytic amount of N,N-dimethylformamide and
optionally using dichloromethane as co-solvent followed by
evaporation and reaction of the acid chlorides with secondary
amines (III) in a solvent like dichloromethane or
N,N-dimethylformamide in the presence of a base like triethylamine
preferably between 0.degree. C. and room temperature or ii) by
suitable amide coupling reactions, such as using of
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU), triethylamine, in N,N-dimethylformamide
preferably between 0.degree. C. and room temperature (step e). Aryl
amino-pyridine amides 11 can be prepared from aryl chloro-pyridine
amides 9 by reaction with a primary or secondary amine in an inert
atmosphere such as argon or nitrogen in the presence of a palladium
catalyst such as tris(dibenzylideneacetone)dipalladium(0)
(Pd.sub.2(dba).sub.3) or palladium(II) acetate
(Pd(COOCH.sub.3).sub.2), a phosphine ligand like
triphenylphosphine,
rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (rac-BINAP) or
(R)-(-)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphos-
phine and a base such as Cs.sub.2CO.sub.3 or KOtert-Bu in a solvent
like toluene, ethanol or water or mixtures thereof preferably in a
temperature range between about 50.degree. C. and the reflux
temperature of the solvents (step f). Aryl amino-pyridine amides 15
(R.sup.6, R.sup.7 equal hydrogen), prepared from the analogous
amino-pyridine amides 11 (R.sup.6 and/or R.sup.7 equal a suitable
protective function; for protecting groups and their use in
synthesis see Protective Groups in Organic Synthesis, T. W. Greene
and P. G. M. Wuts, 3.sup.rd Edition, 1999, Wiley-Interscience) can
be converted into the corresponding mono- or bis-alkanoyl amino
derivatives 11, e.g. by reaction with an acid anhydride in the
presence of a base such as trietylamine in a solvent like acetone
preferably at reflux, or into the corresponding alkanesulfonyl
amino derivatives 11, by reaction with an alkanesulfonyl chloride
in the presence of a base such as trietylamine, a catalyst such as
4-(N,N-dimethyl)-aminopyidine in a solvent like
N,N-dimethylformamide at a temperature around 50.degree. C. and
subsequent treatment with a tetrabutylammonium fluoride solution in
tetrahydrofuran at reflux to cleave potentially formed
bis-sulfonamides into a mono-sulfonamides 11 (step h). Reaction of
aryl chloro-pyridine amides 9 and 10 with a sodium or potassium
alcoholate in the corresponding alcohol as solvent or in a solvent
like tetrahydrofuran preferably at reflux gives aryl
alkoxy-pyridine amides 12 and 18 (steps g). Treatment of aryl
methoxy-pyridine amides 12 with boron tribromide in dichloromethane
preferable between 0.degree. C. and room temperature gives aryl
hydroxy-pyridine amides 16 (step i). Suzuki reactions, as described
for the transformation of halo pyridine esters 1 can be used to
convert aryl chloro-pyridine amides 9 and 10 into aryl pyridine
amides 14 (steps a).). Reaction of aryl chloro-pyridine amides 9
with heteroaromatic compounds carrying an acidic hydrogen atom like
1H-[1,2,4]triazole, 1H-tetrazole, pyridin-2-ol, pyridin-3-ol or
pyridin-4-ol in the presence of a base like sodium hydride in a
solvent like 1-methyl-pyrrolidin-2-one preferably at elevated
temperature in a range between about 100.degree. C. and about
170.degree. C. gives aryl pyridine amides 14 with R.sup.8 equal to
an N-linked heteroaryl or an O-linked heteroaryloxy moiety (steps
k). Reaction of aryl chloro-pyridine amides 9 and 10 with sodium or
potassium cyanide in a solvent like 1-methyl-pyrrolidin-2-one
preferably at elevated temperature in a range between about
100.degree. C. and about 170.degree. C. gives aryl pyridine amides
14 with R.sup.8 or R.sup.2 equal to CN (steps k). Reaction of aryl
chloro-pyridine amides 9 with sodium azide in a solvent like
N,N-dimethylformamide preferably at reflux gives
tetrazolo-pyridines 19 (step 1). Reaction of aryl chloro-pyridine
amides 9 with an alkyl sulfide or a hydrogen sulfide in a solvent
like N,N-dimethylformamide preferably at temperatures between about
60.degree. C. and reflux gives mercapto-pyridines 20 (step m).
##STR00019##
[0161] (In Scheme 2,
##STR00020##
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.9 and m are defined as
described before. R.sup.ii is C.sub.1-6 alkyl, halo C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, optionally substituted heteroaryl,
optionally substituted phenyl-C.sub.1-6 alkyl or optionally
substituted heteroaryl-C.sub.1-6 alkyl or heteroalkyl, said
heteroalkyl optionally carrying a protective function which can be
removed subsequently. R.sup.b is phenyl-methyl).
[0162] Coupling of aryl chloro-pyridine acids 7 with a suitably
protected piperidine e.g. using HATU as described for steps e,
Scheme 1, gives chloro-pyridine-piperdine amides 21 (step a).
Treatment of chloro-pyridine-piperdine amides 21 with a suitable
alcoholate as described for steps g, Scheme 1, results in
alkoxy-pyridine-piperdine amides 22 (step b).
Alkoxy-pyridine-piperdine amides 22 with R.sup.b being an
optionally substituted phenyl-methyl moiety suitable as protective
group can then be converted into hydroxy-pyridine-piperdine amides
23 by standard protocols for removal such protective functions
(step c). Alkylation of hydroxy-pyridine-piperdine amides 23 with a
suitable alkyl or aryl halide in the presence of a base like cesium
or potassium carbonate in a solvent like acetonitrile,
N,N-dimethylformamide, 1-methyl-pyrrolidin-2-one or tetrahydrofuran
at temperatures between room temperature and the reflux temperature
of the solvents gives mixtures of O- and N-alkylated or arylated
pyridine-piperdine amides 24 and 25 (step d). Removal of the acetal
protective function in pyridine-piperdine amides 24 and 25 under
acidic conditions as described in Protective Groups in Organic
Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd Edition, 1999,
Wiley-Interscience, gives ketones 26 and 27 (steps e). Reductive
amination with suitable primary or secondary amines transforms
ketones 26 and 27 into aryl-alkoxy-pyridine amides 28 and
aryl-pyridone-amides 29 under conditions as described for step a in
Scheme 6 (steps f).
##STR00021## ##STR00022##
[0163] (In Scheme 3,
##STR00023##
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.10, R.sup.11 and m are
defined as described before. R.sup.ii is C.sub.1-6 alkyl, halo
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl optionally substituted
heteroaryl, optionally substituted phenyl-C.sub.1-6 alkyl or
optionally substituted heteroaryl-C.sub.1-6 alkyl or heteroalkyl,
said heteroalkyl optionally carrying a protective function which
can be removed subsequently).
[0164] Dichloropyridine carboxylic acids 41 can be esterified (e.g.
using iodomethane, potassium carbonate in N,N-dimethylformamide
preferably at room temperature) and then reacted with sodium
methoxide in dichloromethane preferably between 0.degree. C. and
room temperature to give 6-chloro-2-methoxy-nicotinic acid methyl
esters 42 (steps a, b). Suzuki reactions as described for step a)
in Scheme 1 transform 6-chloro-2-methoxy-nicotinic acid methyl
esters 42 into methoxy-bi-aryl esters 43 (step c). Subsequent
saponification (treatment with lithium or potassium hydroxide in a
solvent like ethanol, methanol, tetrahydrofuran or 2-ethoxy-ethanol
and mixtures thereof in a temperature range between room
temperature and about 150.degree. C.) and coupling with amines
(III) gives methoxy-pyridine amides 44 using procedures similar to
those described for step e, Scheme 1 (steps d, e). Treatment of
methoxy-pyridine amides 44 with boron tribromide in dichloromethane
preferable between 0.degree. C. and room temperature gives
hydroxy-pyridine amides 45 (step f); similar treatment of
methoxy-bi-aryl esters 43 followed by re-esterification (e.g. using
methanol, sulfuric acid at reflux) gives esters 48 (steps f, i).
Hydroxy-pyridine amides 45 can be converted into
trifluoromethanesulfonates 46 (trifluoromethane sulfonic anhydride
and N-ethyldiisopropylamine in a solvent like dichloromethane
preferably in a temperature range between -50.degree. C. and room
temperature, step g). Treatment of trifluoromethanesulfonates 46
with primary or secondary amines under conditions as described for
step f, Scheme 1, gives aryl amino-pyridine-amides 47 (step h).
Alkylation of hydroxy-pyridine esters 48 with a suitable alkyl
halide in the presence of a base like cesium or potassium carbonate
in a solvent like acetonitrile, N,N-dimethylformamide or
tetrahydrofuran gives pyridone esters 49 and alkoxy pyridine esters
50 (step k). Saponification of esters 49 (treatment with lithium or
potassium hydroxide in a solvent like ethanol, methanol,
tetrahydrofuran or 2-ethoxy-ethanol and mixtures thereof in a
temperature range between room temperature and about 150.degree.
C.) and coupling with amines (III) using procedures similar to
those described for step e, Scheme 1, gives aryl-pyridione amides
51 (steps d, e). Reaction of trifluoromethanesulfonates 46 with
sodium azide in a solvent like N,N-dimethylformamide in a
temperature range between RT and reflux gives tetrazolo-pyridines
52 (step l).
##STR00024##
[0165] (In Scheme 4,
##STR00025##
R.sup.1, R.sup.2, R.sup.3, R.sup.10, R.sup.11, R.sup.12 and m are
defined as described before. R.sup.a is C.sub.1-6 alkyl. R.sup.i is
independently hydrogen or C.sub.1-6 alkyl, or both R.sup.is
together form a C.sub.1-6 alkylene group.)
[0166] Alkyl dichloropyridine carboxylates 61 (Scheme 4) undergo
selective substitution of the chloro atom ortho to the ester
function when treated with sodium methylate in a solvent like
tetrahydrofuran preferably around room temperature [Hutchison, A.;
Y., Jun; L., K.; Maynard, G.; Chenard, B. L.; Liu, N.; Guo, Q.;
Guo, Z.; Hrnciar, P. PCT Int. Appl. (2004), WO2004043925A2] (step
a). Suzuki reactions as described for step a) in Scheme 1 transform
chloro-methoxy-pyridine carboxylates 62 into methoxy-bi-aryl esters
63 (step b). Treatment of methoxy-bi-aryl esters 63 with phosphorus
oxychloride and N,N-dimethylformamide preferably at a temperature
around 80.degree. C. gives chloro-bi-aryl esters 64 [Hutchison, A.;
Y., Jun; L., K.; Maynard, G.; Chenard, B. L.; Liu, N.; Guo, Q.;
Guo, Z.; Hrnciar, P. PCT Int. Appl (2004), WO2004043925A2] (step
c). Chloro-bi-aryl esters 64 can undergo Suzuki reactions as
described for step a) in Scheme 1 with boronic acids or esters 65
to give substituted bi-aryl esters 66 (step d). Oxidation of
pyridine esters 66 with meta-chloro-perbenzoic acid preferably in
dichloromethane at room temperature or with hydrogen peroxide urea
adduct and trifluoroacetic anhydride in dichloromethane or
acetonitrile between 0.degree. C. and room temperature gives
N-oxide esters 67 (step e). Treatment of N-oxide esters 67a with
phosphorus oxychloride preferably between about 50.degree. C. and
about 100.degree. C. gives chloro-pyridine esters 68 (step f).
N-oxide esters 67 or chloro pyridine esters 68 can be saponified
and coupled with amines (III) as described for steps d and e,
Scheme 1, (steps g, h) to give N-oxide amides 69 or chloro pyridine
amides 70. Treatment of chloro-pyridine amides 70 with primary or
secondary amines under conditions as described for step f, Scheme
1, gives aryl amino-pyridine-amides 47 (step i).
##STR00026##
[0167] (In Scheme 5,
##STR00027##
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and m are defined as described
before, R.sup.a is C.sub.1-6 alkyl, X is halogen or
trifluoromethylsulfonyloxy.)
[0168] Diazo-beta keto esters 81 are known or can be prepared by
methods known in the art, compare Guillaume, M.; Janousek, Z.;
Viehe, H. G.; Wynants, C.; Declercq, J.-P.; Tinant, B. Journal of
Fluorine Chemistry (1994), 69(3), 253-6. Diazo-beta keto esters 81
react with suitable (triphenyl-phosphanylidene)-acetic acid esters
in solvents like ether or with trialkyl phosphonoacetates, in the
presence of a base like triethylamine and optionally lithium
chloride in a solvent like acetonitrile preferably at room
temperature to give diazo adducts 82 (step a). Subsequent treatment
with triphenylphosphine in ether around room temperature converts
diazo adducts 82 into pyridazine esters 83 [Guillaume, M.;
Janousek, Z.; Viehe, H. G. New trifluoromethylated pyridazines by
reductive cyclization of vinyldiazomethanes bearing a carbonyl
group. Synthesis (1995), (8), 920-2] (step b). Treatment of
pyridazine esters 83 with boron tribromide in dichloromethane
preferably between 0.degree. C. and room temperature removes the
ether and hydrolyzes the ester function; subsequent
re-esterification using sulfuric or hydrochloric acid in the
corresponding alcohol gives hydroxy-pyridazine esters 84 (step c).
Hydroxy-pyridazine esters 84 can be converted into the
corresponding chloro-pyridazine esters 85 by reaction with
phosphorus oxychloride preferably between about 50.degree. C. and
reflux or into the corresponding
trifluoromethanesulfonyloxy-pyridazine esters 85 by treatment with
trifluoromethanesulfonic anhydride and N-ethyldiisopropylamine or
triethylamine in a solvent like dichloromethane preferably in a
temperature range between -50.degree. C. and 0.degree. C. (step d).
Suzuki reactions as described for step a) in Scheme 1 transform
chloro-pyridazine esters 85 or
trifluoromethanesulfonyloxy-pyridazine esters 85 into aryl
pyridazine esters 87 (step f). Alternatively, chloro-pyridazine
esters 85 can be prepared from unsubstituted chloro-pyridazine
esters 86 by an alkylation reaction using a free alkyl radical,
e.g. generated by silver-catalyzed oxidative decarboxylation of an
alkane carboxylic acid and subsequent separation of isomers as
described in Volonterio, A.; Moisan, L.; Rebek, J., Jr. Organic
Letters (2007), 9(19), 3733-3736 (step e). Aryl pyridazine esters
87 can be saponified and coupled with amines (III) as described for
steps d and e, Scheme 1, (steps g, h) to give aryl pyridazine
amides 89.
##STR00028##
[0169] (In Scheme 6,
##STR00029##
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 and m are as defined as
described before.
##STR00030##
is heterocyclyl, which is a non-aromatic mono-cyclic radical of
four to eight ring atoms, in which one ring atom is a nitrogen
atom, the remaining ring atoms being carbon atoms; one of these
carbon atoms is bearing a carbonyl group, said carbon atom is not
directly bonded to the nitrogen atom.
##STR00031##
is heterocyclyl, which is a non-aromatic mono-cyclic radical of
four to eight ring atoms, in which two ring atoms are nitrogen
atoms, the remaining ring atoms being carbon atoms. R.sup.iv and
R.sup.v are independently hydrogen, C.sub.1-6 alkyl, heteroalkyl,
optionally substituted C.sub.3-7 cycloalkyl or optionally
substituted heterocyclyl or
##STR00032##
is optionally substituted heterocyclyl.
##STR00033##
is C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, heteroalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, hydroxy C.sub.3-6 alkenyl, hydroxy
C.sub.3-6 alkynyl, C.sub.1-6 alkoxy C.sub.3-6 alkenyl, C.sub.1-6
alkoxy C.sub.3-6 alkynyl, optionally substituted C.sub.3-7
cycloalkyl, optionally substituted C.sub.3-7 cycloalkyl C.sub.1-6
alkyl, optionally substituted phenyl C.sub.1-6 alkyl, optionally
substituted heteroaryl C.sub.1-6 alkyl, optionally substituted
heterocyclyl or optionally substituted heterocyclyl C.sub.1-6
alkyl.)
[0170] Secondary amines (III) (Scheme 6) are known, can be prepared
by the methods known in the art or the methods described in the
examples or can be prepared e.g. by reductive amination of ketones
101 with secondary amines 102 or by reductive amination of
secondary amines 104 with ketones 105 e.g. by using sodium
triacetoxy-borohydride, sodium cyano-borohydride or borane-pyridine
complex as reagents in the presence of acetic acid and potentially
a base, such as trietylamine, in a solvent, such as
1,2-dichloro-ethane, at temperatures around room temperature (step
a). Such a reductive amination leads to Boc-protected adducts 103
or 106 which are subsequently deprotected by well established
procedures as e.g. trifluoroacetic acid with or without an
additional solvent or alcoholic hydrogen chloride to give secondary
amines (III) (step b). Biaryl carboxylic acids (II) can then be
coupled with secondary amines (III) i) by transformation of the
biaryl carboxylic acids (II) into the corresponding acid chlorides,
preferably by reaction with oxalyl chloride and a catalytic amount
of N,N-dimethylformamide and optionally using dichloromethane as
co-solvent followed by evaporation and reaction of the acid
chlorides with secondary amines (III) in a solvent like
dichloromethane or N,N-dimethylformamide in the presence of a base
like triethylamine preferably between 0.degree. C. and room
temperature or ii) by suitable amide coupling reactions, such as
using of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU), triethylamine, in N,N-dimethylformamide
preferably between 0.degree. C. and room temperature (step c).
During these coupling reactions, OH-functions potentially present
in secondary amines (III) can potentially be protected by a
suitable protective group which is removed after the coupling
reaction or at a later stage of the synthesis.
##STR00034##
[0171] (In Scheme 7,
##STR00035##
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and m are defined as described
before. R.sup.a is C.sub.1-6 alkyl. R.sup.ii is C.sub.1-6 alkyl,
halo C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, optionally substituted
heteroaryl, optionally substituted phenyl-C.sub.1-6 alkyl or
optionally substituted heteroaryl-C.sub.1-6 alkyl or heteroalkyl,
said heteroalkyl optionally carrying a protective function which
can be removed subsequently.)
[0172] Treatment of N-oxides 111 (compare N-oxides 4, Scheme 1)
with trifluoro acetic acid anhydride in a solvent like ethyl
acetate and in the presence of a base like collidine in a
temperature range between about 50.degree. C. and the reflux
temperature of the solvent gives pyridones 112 (step a).
Saponification, e.g. using sodium hydroxide in tetrahydrofuran,
gives acids 113 (step b), which can be coupled with secondary
amines (III) to amides 114 (tautomers of compounds 16) by a variety
of amide coupling reactions, preferably using
di-imidazol-1-yl-methanone as acid activating reagent in a solvent
mixture of acetonitrile and tetrahydrofuran, preferably around room
temperature (step c). Alkylation of pyridones 112 as described for
hydroxy-pyridine-piperdine amides 23 (Scheme 2) gives mixtures of
N- and O-alkylated or arylated pyridine ester compounds 115 and 116
(step d). Alkylated pyridine esters 115 and 116 can be saponified
and coupled to give pyridine amides 28 and 29 (steps b, c).
##STR00036##
[0173] (In Scheme 8,
##STR00037##
R.sup.1, R.sup.2, R.sup.3, R.sup.4, and m are defined as described
before. R.sup.viii is optionally substituted phenyl.)
[0174] Sonogashira reaction of chlorides 9 with a
ethynyl-trimethyl-silane: e.g. by treatment with
bis(triphenylphosphine)palladium(II) dichloride, copper(I) iodide
in triethylamine at a temperature around 125.degree. C. (in a
closed vessel) gives acetylene pyridines 121 (step a). Mild
hydrolysis (e.g. by using potassium carbonate in EtOH/THF 5:1 at
RT) removes the silyl group and gives acetylene pyridines 122 (step
b). Acetylene pyridines 122 react with optionally substituted
benzyl azides in the presence copper(I) iodide and sodium-ascorbate
in a solvent like DMF/H.sub.2O around RT to give benzyl-triazolo
pyridines 123 (step c). Removal of the optionally substituted
benzyl groups, e.g. by treatment with trifluoroacetic acid
preferably at reflux gives unprotected triazolo pyridines 124 (step
d).
##STR00038##
[0175] (In Scheme 9,
##STR00039##
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.13, R.sup.14, and m are
defined as described before.
[0176] Carbonlyation of chlorides 9 e.g. by using
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) as catalyst in a solvent like
MeOH/EtOAc and in the presence of a base like triethylamine in a
temperature range of about 100.degree. C. to 150.degree. C. and 50
to 100 bar CO pressure gives methoxy carbonyl pyridines 131 (step
a). Methoxy carbonyl pyridines 131 can be saponified to carboxy
pyridines 132, e.g. by using lithium hydroxide in a solvent like
THF/MeOH (step b). Carboxy pyridines 132 can be converted into the
corresponding amides 133 by standard amide forming reactions such
as e.g. using O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU), triethylamine, in N,N-dimethylformamide
preferably between 0.degree. C. and room temperature (step c).
Reduction of methyl ester pyridines 131 with lithium borohydride in
a solvent like EtOH gives hydroxymethyl pyridines 134 (step d).
[0177] In addition to the reaction steps explicitly described in
Schemes 1-9, optionally, additional well established synthetic
structural modification can be applied to any substituent at any
stage of the syntheses described, as e.g. introduction and removal
of protective groups.
[0178] As described above, the compounds of formula (I) are CCR-2
receptor antagonists, with some antagonist activity also at CCR-3
and CCR-5. These compounds consequently prevent migration of
various leukocyte populations through the blockade of CCR-2
stimulation. They therefore can be used for the treatment and/or
prevention of inflammatory and/or allergic diseases, such as
peripheral arterial occlusive disease, critical limb ischemia,
vulnerable atherosclerotic plaque patients, unstable angina,
congestive heart failure, left ventricular hypertrophy, ischemia
reperfusion injury, stroke, cardiomyopathy, restenosis, rheumatoid
arthritis, diabetic nephropathy, irritable Bowel Disease, Crohns'
disease, multiple sclerosis, neuropathic pain, atherothrombosis
and/or burns/ulcers in Diabetes/CLI, and asthma.
[0179] Prevention and/or treatment of inflammatory diseases,
particularly peripheral arterial occlusive diseases or
atherothrombosis is the preferred indication.
[0180] The invention therefore also relates to pharmaceutical
compositions comprising a compound as defined above and a
pharmaceutically acceptable excipient.
[0181] The invention likewise embraces compounds as described above
for use as therapeutically active substances, especially as
therapeutically active substances for the treatment and/or
prophylaxis of inflammatory and/or allergic diseases, particularly
as therapeutically active substances for the treatment and/or
prophylaxis of peripheral arterial occlusive disease, critical limb
ischemia, vulnerable atherosclerotic plaque patients, unstable
angina, congestive heart failure, left ventricular hypertrophy,
ischemia reperfusion injury, stroke, cardiomyopathy, restenosis,
rheumatoid arthritis, diabetic nephropathy, irritable Bowel
Disease, Crohns' disease, multiple sclerosis, neuropathic pain,
atherothrombosis, burns/ulcers in Diabetes/CLI, and allergy,
asthma.
[0182] The invention also relates to the use of compounds as
described above for the preparation of medicaments for the
therapeutic and/or prophylactic treatment of inflammatory and/or
allergic diseases, particularly for the therapeutic and/or
prophylactic treatment of peripheral arterial occlusive disease,
critical limb ischemia, vulnerable atherosclerotic plaque patients,
unstable angina, congestive heart failure, left ventricular
hypertrophy, ischemia reperfusion injury, stroke, cardiomyopathy,
restenosis, rheumatoid arthritis, diabetic nephropathy, irritable
Bowel Disease, Crohns' disease, multiple sclerosis, neuropathic
pain, atherothrombosis, burns/ulcers in Diabetes/CLI, and asthma.
Such medicaments comprise a compound as described above.
[0183] The invention also relates to the process and the
intermediates for manufacturing the compounds of formula (I) as
well as the process for manufacturing the intermediates.
[0184] CCR-2 receptor antagonistic activity by the compounds of the
present invention can be demonstrated by the following assays.
Receptor Binding Assay
[0185] Binding assays were done with membranes from CHOK1-CCR2B-A5
cells (Euroscreen) stably overexpressing the human CCR2B.
[0186] Membranes were prepared by homogenizing the cells in 10 mM
Tris pH 7.4, 1 mM EDTA, 0.05 mM benzamidine, leupeptin 6 mg/L and
separating the debris at 1000 g. The membranes were then isolated
at 100000 g in 50 mM Tris pH 7.4, MgCl.sub.2 10 mM, EGTA 1 mM,
glycerol 10%, benzamidine 0.05 mM, leupeptine 6 mg/l.
[0187] For binding, CCR2 antagonist compounds were added in various
concentrations in 50 mM HEPES pH 7.2, 1 mM CaCl.sub.2, 5 mM
MgCl.sub.2, 0.5% BSA, 0.01% NaN.sub.3, together with 100 pM
.sup.125I-MCP-1 (PerkinElmer, 2200 Ci/mmol) to about 5 fMol CCR2
membranes and incubated for 1 hour at room temperature. For
unspecific control 57.7 nM MCP-1 (R&D Systems or prepared at
Roche) was added. Membranes were harvested through GF/B (glass
fiber filter; PerkinElmer) plates, equilibrated with 0.3%
polyethylenimine, 0.2% BSA, air dried and binding was determined by
counting in a topcounter (NXT Packard). Specific binding was
defined as total binding minus nonspecific binding and typically
represents about 90-95% of the total binding. Antagonist activity
is indicated as inhibitor concentration required for 50% inhibition
(IC.sub.50) of specific binding.
Calcium Mobilization Assay
[0188] CHOK1-CCR2B-A5 cells (from Euroscreen) stably overexpressing
the human chemokine receptor 2 isoform B were cultured in Nutrient
Hams F12 medium supplemented with 5% FBS, 100 U/ml penicillin, 100
.mu.g/ml streptomycin, 400 .mu.g/ml G418 and 5 .mu.g/ml
puromycin.
[0189] For the assay cells were grown overnight in 384-well black
clear flat bottom polystyrene plates (Costar) at 37.degree. C. at
5% CO.sub.2. After washing with DMEM, 20 mM Hepes, 2.5 mM
probenecid, 0.1% BSA (DMEM assay buffer) cells were loaded with 4
.mu.M Fluo-4 in the same DMEM assay buffer for 2 hours at
30.degree. C. Excess dye was removed and cells were washed with
DMEM assay buffer. 384-well compound plates were prepared with DMEM
assay buffer/0.5% DMSO with or without various concentrations of
test compounds. Usually compounds were tested for agonist and
antagonist activity.
[0190] Test compounds were added to the assay plate and agonist
activity was monitored as fluorescence for 80 seconds with a FLIPR
(488 nm excitation; 510-570 nm emission; Molecular Devices). After
20-30 min. of incubation at 30.degree. C., 20 nM MCP-1 (R&D;
Roche) was added and fluorescence was monitored again for 80
seconds. Increases in intracellular calcium are reported as maximum
fluorescence after agonist exposure minus basal fluorescence before
exposure. Antagonist activity is indicated as inhibitor
concentration required for 50% inhibition of specific calcium
increases.
[0191] The compounds of general formula (I) exhibit IC50 values in
the Ca mobilisation assay or in the receptor binding assay of 0.1
nM to 10 .mu.M, preferably 1 nM to 1.5 .mu.M for CCR2. The
following table shows measured values in the calcium mobilization
assay for some selected compounds of the present invention.
TABLE-US-00001 Example IC50(.mu.M) Example IC50(.mu.M) 1 0.018 2
0.023 3 0.004 5 0.021 6 0.13 7 0.016 8 0.065 9 0.0064 10 0.078 11
0.071 13 0.058 14 0.012 15 0.25 16 0.0042 17 0.0087 19 0.064 20
0.004 21 0.0032 22 0.018 23 0.041 24 0.0048 25 0.0023 26 0.067 27
0.041 28 0.25 30 0.054 31 0.025 32 0.023 33 0.016 34 0.059 35 0.56
36 0.18 37 0.036 39 0.0058 40 0.0039 41 0.016 42 0.026 43 0.025 44
0.012 45 0.0075 46 0.012 47 0.31 48 0.012 49 0.01 50 0.018 51
0.0055 53 0.015 54 0.12 55 0.13 56 0.013 57 0.21 58 0.19 59 0.49 60
0.29 61 0.32 62 0.069 63 0.032 64 0.3 65 0.0076 66 0.2 67 0.059
[0192] The compounds of formula (I) and/or their pharmaceutically
acceptable salts can be used as medicaments, e.g. in the form of
pharmaceutical preparations for enteral, parenteral or topical
administration. They can be administered, for example, perorally,
e.g. in the form of tablets, coated tablets, dragees, hard and soft
gelatine capsules, solutions, emulsions or suspensions, rectally,
e.g. in the form of suppositories, parenterally, e.g. in the form
of injection solutions or suspensions or infusion solutions, or
topically, e.g. in the form of ointments, creams or oils. Oral
administration is preferred.
[0193] The production of the pharmaceutical preparations can be
effected in a manner which will be familiar to any person skilled
in the art by bringing the described compounds of formula I and/or
their pharmaceutically acceptable salts, optionally in combination
with other therapeutically valuable substances, into a galenical
administration form together with suitable, non-toxic, inert,
therapeutically compatible solid or liquid carrier materials and,
if desired, usual pharmaceutical adjuvants.
[0194] Suitable carrier materials are not only inorganic carrier
materials, but also organic carrier materials. Thus, for example,
lactose, corn starch or derivatives thereof, talc, stearic acid or
its salts can be used as carrier materials for tablets, coated
tablets, dragees and hard gelatine capsules. Suitable carrier
materials for soft gelatine capsules are, for example, vegetable
oils, waxes, fats and semi-solid and liquid polyols (depending on
the nature of the active ingredient no carriers might, however, be
required in the case of soft gelatine capsules). Suitable carrier
materials for the production of solutions and syrups are, for
example, water, polyols, sucrose, invert sugar. Suitable carrier
materials for injection solutions are, for example, water,
alcohols, polyols, glycerol and vegetable oils. Suitable carrier
materials for suppositories are, for example, natural or hardened
oils, waxes, fats and semi-liquid or liquid polyols. Suitable
carrier materials for topical preparations are glycerides,
semi-synthetic and synthetic glycerides, hydrogenated oils, liquid
waxes, liquid paraffins, liquid fatty alcohols, sterols,
polyethylene glycols and cellulose derivatives.
[0195] Usual stabilizers, preservatives, wetting and emulsifying
agents, consistency-improving agents, flavour-improving agents,
salts for varying the osmotic pressure, buffer substances,
solubilizers, colorants and masking agents and antioxidants come
into consideration as pharmaceutical adjuvants.
[0196] The dosage of the compounds of formula (I) can vary within
wide limits depending on the disease to be controlled, the age and
the individual condition of the patient and the mode of
administration, and will, of course, be fitted to the individual
requirements in each particular case. For adult patients a daily
dosage of about 1 to 1000 mg, especially about 1 to 300 mg, comes
into consideration. Depending on severity of the disease and the
precise pharmacokinetic profile the compound could be administered
with one or several daily dosage units, e.g. in 1 to 3 dosage
units.
[0197] The pharmaceutical preparations conveniently contain about
1-500 mg, preferably 1-100 mg, of a compound of formula (I).
[0198] The following Examples serve to illustrate the present
invention in more detail. They are, however, not intended to limit
its scope in any manner.
EXAMPLES
Abbreviations:
[0199] The following are a list of abbreviations and/or acronyms
with their corresponding definitions used in the following
examples: AcOH=Acetic acid, BOC=t-Butyloxycarbonyl,
BuLi=Butyllithium, CDI=1,1-Carbonyldiimidazole,
CH.sub.2Cl.sub.2=Dichloromethane, DCE=1,2-Dichloroethane,
DIBALH=Di-i-butylaluminium hydride,
DCC=N,N'-Dicyclohexylcarbodiimide, DMA=N,N-Dimethylacetamide,
DMAP=4-Dimethylaminopyridine, DMF=N,N-Dimethylformamide,
EDCI=N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride,
EtOAc=Ethylacetate, EtOH=Ethanol, Et.sub.2O=Diethylether,
Et.sub.3N=Triethylamine, eq=Equivalents,
HATU=O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate, HPLC=High performance liquid chromatography,
HOBT=1-Hydroxybenzo-triazole, Huenig's base=iPr.sub.2NEt=N-Ethyl
diisopropylamine, IPC=In process control, LAH=Lithium aluminium
hydride, LDA=Lithium diisopropylamide, LiBH.sub.4=Lithium
borohydride, MeOH=Methanol, NaI=Sodium iodide, Red-Al=Sodium
bis(2-methoxyethoxy)aluminium hydride, RT=room temperature,
TBDMSCl=t-Butyldimethylsilyl chloride, TFA=Trifluoroacetic acid,
THF=Tetrahydrofuran, quant=quantitative.
General Remarks
[0200] All reactions were performed under argon.
Intermediate 1
3-Methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid
A) 3-Methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester
[0201] To a degassed solution of 8.35 g (36.3 mmol) of
5-bromo-3-methyl-pyridine-2-carboxylic acid methyl ester [Wu, G.
G.; Wong, Y.-S.; Poirier, M. Organic Letters (1999), 1(5), 745-747]
in 180 ml of dioxane were added 13.79 g (72.6 mmol) of
3-(trifluoromethyl)phenyl boronic acid and 11.54 g (108.9 mmol) of
sodium carbonate (dissolved in 55 ml of H.sub.2O). While stirring,
1.33 g (1.89 mmol) of
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) was added and the reaction
mixture was stirred at RT for 4 hours, then heated up to 50.degree.
C. After 90 min, it was cooled down to RT, poured into crashed ice
and extracted twice with EtOAc; the organic phases were washed with
water, dried over magnesium sulfate, filtered and evaporated. The
residue was purified by flash column chromatography (heptane/EtOAc
9:1 to 1:1) to give 9.35 g (87%) of the title compound as light
yellow solid. MS: 296.1 (MH.sup.+).
B) 3-Methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid
[0202] To a solution of 1.00 g (3.4 mmol) of
3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester in 40 ml of THF/MeOH (1:1) was added 8.47 ml (8.5
mmol) of lithium hydroxide solution (1 molar in water) and the
reaction mixture was stirred at RT. After 20 hours, the solvents
were evaporated and the residue poured into crashed ice, the pH was
adjusted to 1-2 with HCl 1N and the reaction mixture was extracted
twice with EtOAc; the organic phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. The residue was
purified by re-crystallization from CH.sub.2Cl.sub.2/heptane to
give 0.94 g (99%) of the title compound as colorless solid. MS:
280.0 (M-H.sup.-).
C)
3-Methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid
[0203] To a solution of 0.48 g (1.7 mmol) of
3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid in
15 ml of CH.sub.2Cl.sub.2 was added 1.23 g (5.2 mmol) of
3-chloro-perbenzoic acid and the reaction mixture was stirred for 3
days at RT. Then, it was filtered, the filtrate was evaporated and
the residue purified by flash column chromatography (heptane/EtOAc
4:1 to 0:1) to give 0.33 g (66%) of the title compound as light
yellow solid. MS: 296.3 (M-H.sup.-).
Intermediates 2 and 3
6-Chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester (Intermediate 2) and
4-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester (Intermediate 3)
[0204] 3.48 g (11.2 mmol) of
3-methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester [prepared from
3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester (intermediate 1A) by reaction with 3-chloro-perbenzoic
acid in analogy to the procedure described for the preparation of
intermediate 1C] was added at RT while stirring to 20.4 ml=34.25 g
(223.3 mmol) of phosphorus oxychloride and the reaction mixture was
warmed up to 50.degree. C. After 2 hours, it was cooled down to RT
and poured into crashed ice. This solution was carefully
neutralized with solid sodium carbonate and extracted twice with
EtOAc; the organic phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (heptane/CH.sub.2Cl.sub.2
1:1 to 0:1) to give 2.52 g (68%)
6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester as light yellow oil; [MS: 330.0 (MH.sup.+, 1Cl)]
and 1.10 g (30%)
4-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxyli-
c acid methyl ester as colorless solid. MS: 330.0 (MH.sup.+,
1Cl).
Intermediate 4
N-{5-Methyl-6-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]-3-[3-(trifluorom-
ethyl)phenyl]pyridin-2-yl}-N-(methylsulfonyl)methanesulfonamide
[0205] A solution of 0.22 g (0.5 mmol) of
[6-amino-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone (example 7) in 5.0 ml of DMF was
treated with 0.43 ml=0.309 g (3.1 mmol) of Et.sub.3N and 0.006 g
(0.05 mmol) of DMAP. To the stirred solution was added 0.08 ml=0.12
g (1.0 mmol) of methanesulfonyl chloride drop by drop and the
reaction mixture was subsequently warmed up to 50.degree. C. After
5 hours, it was poured into crashed ice and extracted twice with
EtOAc; the organic phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0
to 4:1) to give 0.13 g (44%) of the title compound as yellow solid.
MS: 589.1 (MH.sup.+).
Intermediate 5
1,4-Dimethyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-car-
boxylic acid
A) 2,6-Dichloro-4-methyl-nicotinic acid methyl ester
[0206] To a solution of 8.05 g (39.1 mmol) of
2,6-dichloro-4-methyl-nicotinic acid [Lamm, G. Ger. Offen. (1977),
DE 2538950] in 100 ml of DMF was added 8.10 g (58.6 mmol) of
potassium carbonate. While stirring, 12.16 ml=27.7 g (195.4 mmol)
of iodomethane was added drop by drop and the reaction mixture was
stirred for 6 hours at RT. It was then poured into crashed ice and
extracted twice with EtOAc; the organic phases were washed with
water, dried over magnesium sulfate, filtered and evaporated to
give 8.47 g (99%) of the title compound as light yellow solid. MS:
219.0 (M.sup.+, 2Cl).
B) 6-Chloro-2-methoxy-4-methyl-nicotinic acid methyl ester
[0207] To a solution of 6.50 g (29.5 mmol) of
2,6-dichloro-4-methyl-nicotinic acid methyl ester in 75 ml of
CH.sub.2Cl.sub.2 was added at 0.degree. C. 6.56 ml (35.4 mmol) of a
sodium methoxide solution (5.4 molar in MeOH). After 16 hours, the
reaction mixture was warmed up to RT and stirred again 16 hours at
this temperature and subsequently poured into crashed ice; then,
the pH was adjusted to 4-5 with 2N acetic acid and the reaction
mixture was extracted twice with CH.sub.2Cl.sub.2; the organic
phases were washed with water, dried over magnesium sulfate,
filtered and evaporated. The residue was purified by flash column
chromatography (heptane/EtOAc 1.0 to 98:2) to give 5.79 g (91%) of
the title compound as colorless solid. MS: 216.1 (MH.sup.+,
1Cl).
C) 2-Methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid
methyl ester
[0208] To a solution of 5.75 g (26.7 mmol) of
6-chloro-2-methoxy-4-methyl-nicotinic acid methyl ester in 250 ml
of DMF was added 10.13 g (53.3 mmol) of
3-trifluoromethyl-phenyl-boronic acid followed by 50.0 ml of a
solution of tribasic potassium phosphate (2 M in water). Finally,
1.54 g (1.3 mmol) of tetrakis-(triphenylphosphine)-palladium was
added and the reaction mixture was subsequently warmed up to
80.degree. C. After 5 hours, it was cooled down to RT, poured into
crashed ice and extracted twice with CH.sub.2Cl.sub.2; the organic
phases were washed with water, dried over magnesium sulfate,
filtered and evaporated. The residue was purified by flash column
chromatography (heptane/EtOAc 1:0 to 9:1) to give 8.54 g (98%) of
the title compound as light yellow oil. MS: 326.1 (MH.sup.+).
D) 2-Hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid
and
4-Methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carbox-
ylic acid (tautomers)
[0209] A solution of 0.325 g (1.0 mmol) of
2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid
methyl ester in 10 ml of CH.sub.2Cl.sub.2 was cooled down to
0.degree. C., 2.0 ml (2.0 mmol) of a solution of boron tribromide
(1 molar in CH.sub.2Cl.sub.2) was added drop by drop and the
reaction mixture was subsequently warmed up to RT. After two hours,
1.0 ml of MeOH was added and 90 min later, the reaction mixture was
evaporated. The crude intermediate formed was used without
purification in the next step.
E) 2-Hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid
methyl ester and 4-Methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1
2-dihydro-pyridine-3-carboxylic acid methyl ester tautomers
[0210] A solution of 0.30 g (1.0 mmol) of
2-hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic
acid/4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-c-
arboxylic acid in 15 ml of MeOH was treated with 0.06 ml=0.01 g
(0.1 mmol) of H.sub.2SO.sub.4 (98%) and the reaction mixture was
heated up to reflux. After 4 hours, it was cooled down to RT,
poured into crashed ice and extracted twice with CH.sub.2Cl.sub.2;
the organic phases were washed with water, dried over magnesium
sulfate, filtered and evaporated. The residue was purified by flash
column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0 to 9:1) to give
0.24 g (77%) of the title compound as off-white solid. MS: 312.0
(MH.sup.+).
F)
1,4-Dimethyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3--
carboxylic acid methyl ester
[0211] A solution of 0.62 g (2.0 mmol) of
2-hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid
methyl
ester/4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3--
carboxylic acid methyl ester in 20 ml of DMF was treated with 0.78
g (2.4 mmol) of cesium carbonate, followed by 0.62 ml=1.41 g (10.0
mmol) of iodomethane. This mixture was stirred for 70 hours at RT,
then poured into crashed ice and extracted twice with
CH.sub.2Cl.sub.2; the organic phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (heptane/EtOAc 4:1 to 0:1)
to give 0.21 g (33%) of the title compound as light yellow solid;
[MS: 326.1 (MH.sup.+)] and 0.42 g (65%) of
2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid
methyl ester as light yellow oil. MS: 326.1 (MH.sup.+).
G)
1,4-Dimethyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3--
carboxylic acid
[0212] To a solution of 0.60 g (1.8 mmol) of
1,4-dimethyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-ca-
rboxylic acid methyl ester 4.0 ml of THF/MeOH (1:1) was added 11.0
ml (11.0 mmol) of lithium hydroxide solution (1 molar in water) and
the reaction mixture was then heated up to 60.degree. C. After 7
hours, the solvents were evaporated and the residue poured into
crashed ice, acidified with 2N HCl and extracted twice with
CH.sub.2Cl.sub.2; the organic phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0
to 95:5) to give 0.53 g (94%) of the title compound as light yellow
solid. MS: 310.1 (M-H.sup.-).
Intermediate 6
Benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester
A) 4-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester
[0213] A solution of 10.0 g (50.2 mmol) of
4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 6.00
ml=6.15 g (60.2 mmol) of (S)-(-)-pyrrolidin-2-yl-methanol in 100.0
ml of EtOH was treated with 100.0 ml of 1,2-dichloroethane,
followed by 7.53 ml (60.2 mmol) of borane-pyridine complex (8
molar). Then, 7.46 ml=7.84 g (130.5 mmol) of acetic acid was added
to this solution. After stirring at RT for 16 hours, the reaction
mixture was poured into crashed ice; then, the pH was adjusted to
9-10 with sodium carbonate solution and the mixture was extracted
twice with EtOAc; the combined organic phases were washed with
water, dried over MgSO.sub.4, filtered and evaporated. The residue
was purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH
1:0 to 9:1) to give 10.4 g (73%) of the title compound as light
yellow oil. MS: 285.1 (MH.sup.+).
B)
4-((S)-2-Benzoyloxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester
[0214] 3.35 g (11.8 mmol) of
4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester was dissolved in 55 ml of THF at RT and
treated with 0.57 g (13.0 mmol) of sodium hydride (55% in mineral
oil). 1.68 ml=2.03 g (14.1 mmol) of benzoyl chloride was added drop
by drop and stirring continued for 2 hours. The reaction mixture
was then poured into crashed ice and extracted three times with
EtOAc; the organic phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0
to 95:5) to give 2.80 g (61%) of the title compound as yellow oil.
MS: 389.3 (MH.sup.+).
C) Benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl
ester
[0215] To a solution of 2.78 g (7.2 mmol) of
4-((S)-2-benzoyloxymethyl-pyrrolidin-1-yl)-piperidine-1-carboxylic
acid tert-butyl ester in 80 ml of CH.sub.2Cl.sub.2 was added 5.83
ml of TFA (90% in water) drop by drop. After 16 hours, the reaction
mixture was poured into crashed ice; then, the pH was adjusted to
9-10 with sodium carbonate solution and the mixture was extracted
three times with CH.sub.2Cl.sub.2; the organic phases were washed
with water, dried over magnesium sulfate, filtered and evaporated.
The residue was purified by flash column chromatography
[CH.sub.2Cl.sub.2 (sat. with NH.sub.3)/MeOH 1:0 to 9:1] to give
1.96 g (95%) of the title compound as yellow oil. MS: 289.1
(MH.sup.+).
Intermediates 7, 8 and 9
3-Chloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester (Intermediate 7),
3,5-bis-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester (Intermediate 8) and
5-chloro-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester (Intermediate 9)
[0216] To a degassed solution of 10.48 g (50.9 mmol) of
3,5-dichloro-pyridine-2-carboxylic acid methyl ester [prepared in
analogy to the procedure described for the preparation of
intermediate 5A from 3,5-dichloro-pyridine-2-carboxylic acid and
iodomethane, potassium carbonate in DMF] in 400 ml of
dimethoxyethane were added 14.49 g (76.3 mmol) of
3-(trifluoromethyl)phenyl boronic acid and 49.73 g (152.6 mmol) of
caesium carbonate. While stirring, 0.77 g (1.50 mmol) of
[(t-Bu).sub.2P(OH)].sub.2PdCl.sub.2 (POPd) was added and the
reaction mixture was stirred at reflux for 7 hours. It was then
cooled down to RT, poured into crashed ice and extracted twice with
EtOAc; the organic phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (heptane/EtOAc 98:2 to 1:1)
to give 3.22 g (20%) of
3-chloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester as light yellow oil; [MS: 316.0 (MH.sup.+, 1Cl)] and
2.80 g (12.9%) of
3,5-bis-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester as light yellow solid; [MS: 426.1 (MH.sup.+)] and 3.21
g (20.0%) of
5-chloro-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester as light yellow oil. [MS: 316.0 (MH.sup.+, 1Cl)].
Intermediate 10
Trifluoro-methanesulfonic acid
4-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-6-(3-trifluoromethyl-
-phenyl)-pyridin-2-yl ester
A) 2-Methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic
acid
[0217] To a solution of 0.325 g (1.00 mmol) of
2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid
methyl ester (intermediate 5C) in 20 ml of THF/MeOH (1:1) was added
2.50 ml (2.50 mmol) of lithium hydroxide solution (1 molar in
water) drop by drop and the reaction mixture was then heated up to
reflux. After 8 hours, it was poured into crashed ice and acidified
with HCl/H.sub.2O (1N) to pH 3.0 and then extracted twice with
EtOAc; the organic phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0
to 4:1) to give 0.24 g (77%) of the title compound as light yellow
solid. MS: 310.0 (M-H.sup.-).
B)
[2-Methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrro-
lidin-1-yl-piperidin-1-yl)-methanone
[0218] A suspension of 0.200 g (0.64 mmol)
2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid in 5
ml of CH.sub.2Cl.sub.2 was treated at RT with one drop of DMF;
then, 0.06 ml=0.09 g (0.71 mmol) of oxalyl chloride was added to
this solution drop by drop below 25.degree. C. and the reaction
mixture was stirred for 0.5 hour. After removal of the solvents by
evaporation in a high vacuum, the residue was dissolved again in 10
ml of CH.sub.2Cl.sub.2 and 0.36 ml=0.26 g (2.57 mmol) of Et.sub.3N
was added while stirring, followed by 0.099 g (0.64 mmol) of
4-pyrrolidin-1-yl-piperidine. The reaction mixture was stirred at
RT. After 16 hours, it was poured into crashed ice and extracted
twice with CH.sub.2Cl.sub.2; the organic phases were washed with
water, dried over magnesium sulfate, filtered and evaporated. The
residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH 98:2 to 4:1) to give 0.278 g (97%) of the
title compound as yellow amorphous solid. MS: 448.1 (MH.sup.+).
C)
[2-Hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrro-
lidin-1-yl-piperidin-1-yl)-methanone;
4-Methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-6-(3-trifluoromethyl-
-phenyl)-1H-pyridin-2-one (tautomers)
[0219] A solution of 5.25 g (11.7 mmol) of
[2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone in 180 ml of CH.sub.2Cl.sub.2
was cooled down to 0.degree. C. and 23.5 ml (23.5 mmol) of a boron
tribromide solution (1 molar in CH.sub.2Cl.sub.2) was added drop by
drop. After stirring for 1 hour at RT, the reaction mixture was
added drop by drop to a cold solution of NaHCO.sub.3 (saturated in
water) and it was then extracted twice with MeCl.sub.2; the organic
phases were washed with water, dried over magnesium sulfate,
filtered and evaporated. The residue was purified by flash column
chromatography (CH.sub.2Cl.sub.2/MeOH 98:2 to 4:1) to give 4.96 g
(98%) of the title compound as light yellow solid. MS: 434.3
(MH.sup.+).
D) Trifluoro-methanesulfonic acid
4-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-6-(3-trifluoromethyl-
-phenyl)-pyridin-2-yl ester
[0220] 0.34 ml=0.256 g (2.0 mmol) of N-ethyldiisopropylamine was
added to a solution of 0.43 g (1.0 mmol) of
[2-hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone;
4-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-6-(3-trifluoromethyl-
-phenyl)-1H-pyridin-2-one (tautomers) in 10 ml of CH.sub.2Cl.sub.2
at RT. While stirring 0.24 ml=0.42 g (1.50 mmol) of
trifluoromethanesulfonic anhydride were added to this suspension
drop by drop which resulted in a clear solution. After 20 hours,
the reaction mixture was poured into crashed ice and extracted
twice with CH.sub.2Cl.sub.2; the organic phases were washed with
water, dried over magnesium sulfate, filtered and evaporated. The
residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH 1:0 to 9:1) to give 0.21 g (37%) of the
title compound as light brown amorphous solid. MS: 566.4
(MH.sup.+).
Intermediate 11
3,6-Dichloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester
A)
3-Chloro-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester
[0221] A suspension of 1.997 g (6.3 mmol) of
3-chloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester (intermediate 7) in 50 ml of MeCN was treated at RT
with 1.25 g (13.3 mmol) of hydrogen peroxide urea adduct and the
reaction mixture was stirred for 1 hour. It was then cooled down to
0.degree. C. and 1.79 ml=2.71 g (12.6 mmol) of trifluoroacetic
anhydride (98%) were added drop by drop below 3.degree. C. The
reaction mixture was then warmed up to RT, stirred for 3 hours and
poured into crashed ice and extracted twice with CH.sub.2Cl.sub.2;
the organic phases were washed with water, dried over magnesium
sulfate, filtered and evaporated. The residue was purified by flash
column chromatography (heptane/EtOAc 1:0 to 3:2) to give 1.83 g
(87%) of the title compound as colorless solid. MS: 332.0
(MH.sup.+, 1Cl).
B) 3,6-Dichloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester
[0222] In analogy to the procedure described for the preparation of
intermediates 2 and
3,3-chloro-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester was reacted with phosphorus oxychloride at
50.degree. C. to give the title compound (major isomer) as light
yellow solid. MS: 350.1 (MH.sup.+, 2Cl); and
3,4-dichloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester (minor isomer) as colorless oil. MS: 350.1
(MH.sup.+, 2Cl).
Intermediate 12
[3-Methyl-5-(3-trifluoromethyl-phenyl)-6-trimethylsilanylethynyl-pyridin-2-
-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
[0223] 0.90 g (1.99 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3), 0.042 g (0.06 mmol)
of bis(triphenylphosphine)palladium(II) chloride and 0.021 g (0.11
mmol) of copper(I) iodide were suspended in 2.0 ml of
triethylamine. After addition of 2.14 ml=1.50 g (15.0 mmol) of
ethinyltrimethylsilane, the reaction vessel was sealed, heated up
to 125.degree. C. and stirring continued for four days. The
reaction mixture was then poured into crashed ice and extracted
three times with CH.sub.2Cl.sub.2; the organic phases were washed
with water, dried over magnesium sulfate, filtered and evaporated.
The residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH 1:0 to 9:1) to give 0.693 g (68%) of the
title compound as dark brown oil. MS: 514.4 (MH.sup.+).
Intermediate 13
[6-[1-(4-Methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-3-methyl-5-(3-trifluorome-
thyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
[0224] A solution of 0.30 g (0.68 mmol) of
[6-ethynyl-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone (example 24) and 0.116 g (0.71
mmol) of 1-azidomethyl-4-methoxy-benzene in 3.0 ml of DMF was
treated with 0.013 g (0.066 mmol) of (+)-sodium-L-ascorbate and
0.129 g (0.68 mmol) of copper(I) iodide in 1.0 ml of H.sub.2O and
the reaction was stirred at RT for 2 hours. Then, the solvents were
removed by evaporation in high vacuum, the residue was diluted with
H.sub.2O/NH.sub.4OH (25%) and extracted twice with
CH.sub.2Cl.sub.2; the organic phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0
to 95:5) to give 0.363 g (88%) of the title compound as light brown
oil. MS: 605.4 (MH).
Intermediate 14
[6-(2-Benzyloxy-ethylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin--
2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
[0225] In analogy to the procedure described for the preparation of
example 6,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
2-benzyloxy-ethylamine,
[rac]-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, palladium(II)
acetate and cesium carbonate in toluene at reflux to give the title
compound as yellow oil. MS: 567.4 (MH.sup.+).
Intermediate 15
6-Hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid;
3-Methyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2--
carboxylic acid (tautomers)
A)
3-Methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester
[0226] 260 g (881 mmol)
3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester (intermediate 1A) were dissolved in 5 l
dichloromethane at 20.degree. C. 325.6 g (1321 mmol)
m-chloroperbenzoic acid (mCPBA) were added in portions over 40 min.
The yellow turbid solution was stirred for 30 min at 20-22.degree.
C. and heated to 30.degree. C. for 5 h (IPC by HPLC, additional
mCPBA can be added if the conversion is not sufficient) then
overnight at RT. The reaction mixture was washed twice with half
saturated Na.sub.2CO.sub.3 (6 l and 4 l), then with 4 l 5% aqueous
NaCl solution. The organic phase was treated with 150 ml morpholine
(1722 mmol) and stirred at RT for 45 min (peroxide test negative).
The orange turbid solution was washed twice with 6 l water, dried
over Na.sub.2SO.sub.4 and filtered. The filter cake was washed with
1 l dichloromethane. The filtrate was concentrated to an oil. 1 l
2-methoxy-2-methyl-propane was added upon which crystallization
started. The suspension was cooled overnight to -10.degree. C.
After 10 h at -10.degree. C., the suspension was filtered and
washed with cold 2-methoxy-2-methyl-propane. The filter cake was
dried under reduced pressure (45.degree. C./10 mbar) to give 222.7
g (81%) of the title compound as colorless crystals. MS: 312.0
(MH.sup.+).
B)
6-Hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester;
3-Methyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2-carbox-
ylic acid methyl ester (tautomers)
[0227] 20 g (64.25 mmol) of
3-methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester were dissolved in 400 ml ethyl acetate. 13.8 ml
(103 mmol) 2,4,6-trimethylpyridine were added and the solution was
heated to 60.degree. C. 14.6 ml (103 mol) trifluoroacetic anhydride
were added over 1 h. After an additional reaction time of 2 h (IPC
by HPLC), the reaction mixture was cooled to RT. A solution of 13.1
ml (321 mmol) methanol in 16 ml ethyl acetate was added slowly
during which a suspension was obtained. The suspension was stirred
at RT for 1 h. About 200 ml solvent were removed at the rotavap and
the suspension was stirred for 30 min at RT. The crystals were
filtered, washed with ethyl acetate and dried under reduced
pressure (50.degree. C./10 mbar) to give 18.04 g (90%) of the title
compound as a light yellow powder. MS: 312.0 (MH.sup.+).
C)
6-Hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid;
3-Methyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2--
carboxylic acid (tautomers)
[0228] 18 g (57.8 mmol) of
6-hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl
ester/3-methyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2--
carboxylic acid methyl ester (tautomers) were suspended in 144 ml
of THF. 34.7 ml (69.4 mmol) of a 2 M aqueous NaOH solution were
added. The resulting solution was heated to 40.degree. C. and
stirred at that temperature until complete conversion (ca 7 h, IPC
by HPLC). The reaction mixture was cooled to RT. 34.7 ml of a 2 M
aqueous HCl solution were added (pH 2) upon which a suspension was
obtained. The suspension was stirred for 2 h at RT and filtered.
The filter cake was washed with water and dried under reduced
pressure (50.degree. C./10 mbar) to give 16.29 g (95%) of the title
compound as colorless crystals. MS: 296.0 (M-H.sup.-).
Example 1
[3-Methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-pi-
peridin-1-yl)-methanone
##STR00040##
[0230] To a solution of 0.42 g (1.5 mmol) of
3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
(intermediate 1B) in 15 ml of DMF was added 0.60 g (1.6 mmol) of
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU) and 0.62 ml=0.45 g (4.5 mmol) of
Et.sub.3N; after 30 min, 0.24 g (1.6 mmol) of
4-pyrrolidin-1-yl-piperidine was added. 1 hour later, the reaction
mixture was poured into crashed ice and extracted three times with
EtOAc; the organic phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 95:5
to 4:1) to give 0.56 g (89%) of the title compound as light brown
oil. MS: 418.1 (MH.sup.+).
Example 2
[3-Methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-
-yl-piperidin-1-yl)-methanone
##STR00041##
[0232] In analogy to the procedure described for example 1,
3-methyl-1-oxy-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid (intermediate 1) was reacted with 4-pyrrolidin-1-yl-piperidine
to give the title compound as light brown solid. MS: 434.3
(MH.sup.+).
Example 3
[6-Chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone
##STR00042##
[0234] In analogy to the procedure described for example 1,
6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid [prepared from
6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester (intermediate 2) by saponification in analogy to
the procedure described for intermediate 1B] was reacted with
4-pyrrolidin-1-yl-piperidine to give the title compound as light
brown solid. MS: 452.1 (MH.sup.+, 1Cl).
Example 4
[4-Chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone
##STR00043##
[0236] In analogy to the procedure described for example 1,
4-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid [prepared from
4-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester (intermediate 3) by saponification in analogy to
the procedure described for intermediate 1B] was reacted with
4-pyrrolidin-1-yl-piperidine to give the title compound as
colorless solid. MS: 452.1 (MH.sup.+, 1Cl).
Example 5
[4-((S)-2-Hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[3-methyl-5-(3-tr-
ifluoromethyl-phenyl)-pyridin-2-yl]-methanone
##STR00044##
[0238] In analogy to the procedures described for example 1 and for
intermediate 1B,
3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
(intermediate 1B) was reacted with benzoic acid
(S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 6)
to give benzoic acid
(S)-1-{1-[3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carbonyl]-pipe-
ridin-4-yl}-pyrrolidin-2-ylmethyl ester, which was subsequently
saponified to give the title compound as light brown solid. MS:
448.1 (MH.sup.+).
Example 6
[6-(4-Methoxy-benzylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-
-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00045##
[0240] A suspension of 1.25 g (2.8 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3), 0.069 g (0.1 mmol)
of [rac]-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 0.025 g (0.1
mmol) of palladium(II) acetate and 0.40 g (2.9 mmol) of
4-methoxy-benzylamine in 30 ml of toluene was stirred at RT; 1.08 g
(3.3 mmol) of cesium carbonate was added and the reaction mixture
subsequently heated up to reflux. After 18 hours, it was cooled
down to RT, poured into crashed ice and extracted twice with EtOAc;
the organic phases were washed with water, dried over magnesium
sulfate, filtered and evaporated. The residue was purified by flash
column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0 to 9:1) to give
1.25 g (82%) of the title compound as light yellow solid. MS: 553.3
(MH.sup.+).
Example 7
[6-Amino-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-
-1-yl-piperidin-1-yl)-methanone
##STR00046##
[0242] To a solution of 1.48 g (2.7 mmol) of
[6-(4-methoxy-benzylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin--
2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 6) in
75 ml of CH.sub.2Cl.sub.2 was added 12.2 ml=18.2 g (160 mmol) of
trifluoroacetic acid and the reaction mixture was subsequently
heated up to reflux. After two hours, it was poured into crashed
ice, the pH was adjusted to 8-9 with sodium carbonate solution and
it was extracted twice with CH.sub.2Cl.sub.2; the organic phases
were washed with water, dried over magnesium sulfate, filtered and
evaporated. The residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH 98:2 to 3:1) to give 1.04 g (90%) of the
title compound as light yellow foam. MS: 433.3 (MH.sup.+).
Example 8
[6-Methoxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone
##STR00047##
[0244] A solution of 0.55 g (1.2 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) in 10 ml of MeOH was
treated with 2.25 ml (12.2 mmol) of a sodium methoxide solution
(5.4 molar in MeOH) and the reaction mixture was heated up to
reflux. After 18 hours, it was poured into crashed ice and
extracted three times with CH.sub.2Cl.sub.2/2-propanol 4:1; the
organic phases were dried over magnesium sulfate, filtered and
evaporated. The residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH 98:2 to 4:1) to give 0.41 g (76%) of the
title compound as light yellow oil. MS: 448.3 (MH.sup.+).
Example 9
[6-Hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone;
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-1H-pyridin-2-one (tautomers)
##STR00048##
[0246] A solution of 0.20 g (0.4 mmol) of
[6-methoxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone (example 8) in 10 ml of
CH.sub.2Cl.sub.2 was cooled down to 0.degree. C. and 0.89 ml (0.9
mmol) of a solution of boron tribromide (1 molar in
CH.sub.2Cl.sub.2) was added drop by drop and the reaction mixture
was subsequently warmed up to RT. After three hours, 1.0 ml of MeOH
was added and 30 min later, it was poured into crashed ice,
neutralized with sodium hydrogen carbonate and extracted twice with
CH.sub.2Cl.sub.2; the organic phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 98:2
to 3:1) to give 0.077 g (40%) of the title compound as off-white
solid. MS: 434.2 (MH.sup.+).
Example 10
N-Acetyl-N-[5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trif-
luoromethyl-phenyl)-pyridin-2-yl]-acetamide
##STR00049##
[0247] Example 11
N-[5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluorometh-
yl-phenyl)-pyridin-2-yl]-acetamide
##STR00050##
[0249] A solution of 0.22 g (0.5 mmol) of
[6-amino-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone (example 7) in 5 ml of acetone was
treated with 0.35 ml=0.26 g (2.5 mmol) of Et.sub.3N, followed by
0.19 ml=0.21 g (2.0 mmol) of acetic anhydride and the reaction
mixture was subsequently heated up to reflux. After 22 hours, it
was poured into crashed ice, the pH was adjusted to 8-9 with sodium
carbonate solution and it was extracted twice with EtOAc; the
organic phases were washed with water, dried over magnesium
sulfate, filtered and evaporated. The residue was purified by flash
column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0 to 3:2) to give
0.12 g (51%) the
N-[5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromet-
hyl-phenyl)-pyridin-2-yl]-acetamide as light yellow solid [MS:
475.2 (MH.sup.+)] and 0.098 g (37%) of
N-acetyl-N-[5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-tri-
fluoromethyl-phenyl)-pyridin-2-yl]-acetamide as yellow solid. MS:
517.2 (MH.sup.+).
Example 12
N-[5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluorometh-
yl-phenyl)-pyridin-2-yl]-methanesulfonamide
##STR00051##
[0251] To a solution of 0.13 g (0.2 mmol) of
N-{5-methyl-6-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]-3-[3-(trifluoro-
methyl)phenyl]pyridin-2-yl}-N-(methylsulfonyl)methanesulfonamide
(intermediate 4) in 2.0 ml of THF was added 0.2 ml (0.2 mmol) of a
tetrabutylammonium fluoride solution (1M in THF) and the reaction
mixture was subsequently heated up to reflux. After 4 days, the
solvent was evaporated and the crude product purified by flash
column chromatography (CH.sub.2Cl.sub.2/MeOH 98:2 to 4:1) to give
0.069 g (64%) of the title compound as yellow amorphous solid. MS:
511.3 (MH.sup.+).
Example 13
1,4-Dimethyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-6-(3-trifluoromet-
hyl-phenyl)-1H-pyridin-2-one
##STR00052##
[0253] A solution of 0.16 g (0.5 mmol) of
1,4-dimethyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-ca-
rboxylic acid (intermediate 5) in 5 ml of CH.sub.2Cl.sub.2 was
treated at RT with two drops of DMF; then, 0.05 ml=0.074 g (0.6
mmol) of oxalyl chloride was added and the reaction mixture was
stirred for 30 min at RT. After removal of the solvents by
evaporation in a high vacuum, the residue was dissolved again in 10
ml of CH.sub.2Cl.sub.2 and the solution was cooled down to
0.degree. C.; then, 0.29 ml=0.21 g (2.1 mmol) of Et.sub.3N was
added while stirring, followed by 0.081 g (0.5 mmol) of
4-pyrrolidin-1-yl-piperidine. The reaction mixture was subsequently
warmed up to RT. After 3 hours, it was poured into crashed ice and
extracted twice with CH.sub.2Cl.sub.2; the organic phases were
washed with water, dried over magnesium sulfate, filtered and
evaporated. The residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH 98:2 to 95:5) to give 0.20 g (85%) of the
title compound as light yellow solid. MS: 448.2 (MH.sup.+).
Example 14
[3-Chloro-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-pi-
peridin-1-yl)-methanone
##STR00053##
[0255] In analogy to the procedure described for example 1,
3-chloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
[prepared from
3-chloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester (intermediate 7) by saponification in analogy to the
procedure described for intermediate 1B] was reacted with
4-pyrrolidin-1-yl-piperidine to give the title compound as light
yellow oil. MS: 438.2 (MH.sup.+, 1Cl).
Example 15
[3,5-Bis-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piper-
idin-1-yl)-methanone
##STR00054##
[0257] In analogy to the procedure described for example 1,
3,5-bis-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
[prepared from
3,5-bis-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid
methyl ester (intermediate 8) by saponification in analogy to the
procedure described for intermediate 1B] was reacted with
4-pyrrolidin-1-yl-piperidine to give the title compound as light
yellow oil. MS: 548.3 (MH.sup.+).
Example 16
[5-Methyl-3-(3-trifluoromethyl-phenyl)-[2,3']bipyridinyl-6-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone
##STR00055##
[0259] In analogy to the procedure described for the preparation of
intermediate 5C,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
pyridine-3-yl-boronic acid to give the title compound as colorless
oil. MS: 495.3 (MH.sup.+).
Example 17
[3-Methyl-6-pyrimidin-5-yl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-p-
yrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00056##
[0261] In analogy to the procedure described for the preparation of
intermediate 5C,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
pyrimidine-5-yl-boronic acid to give the title compound as
off-white amorphous solid. MS: 496.2 (MH.sup.+).
Example 18
[2-(4-Methoxy-benzylamino)-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-
-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00057##
[0263] In analogy to the procedure described for the preparation of
example 6, trifluoro-methanesulfonic acid
4-methyl-3-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-6-(3-trifluoromethyl-
-phenyl)-pyridin-2-yl ester (intermediate 10) was reacted with
[rac]-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, palladium(II)
acetate and 4-methoxy-benzylamine to give the title compound as
yellow oil. MS: 553.4 (MH.sup.+).
Example 19
[2-Amino-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-(4-pyrrolidin-
-1-yl-piperidin-1-yl)-methanone
##STR00058##
[0265] In analogy to the procedure described for the preparation of
example 7,
[2-(4-methoxy-benzylamino)-4-methyl-6-(3-trifluoromethyl-phenyl)-pyridin--
3-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 18) was
reacted with trifluoroacetic acid to give the title compound as
light yellow solid. MS: 433.5 (MH.sup.+).
Example 20
[6-(3-Chloro-[1,2,4]triazol-1-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-py-
ridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00059##
[0267] A well stirred solution of 0.17 g (1.59 mmol) of
3-chloro-1H-[1,2,4]triazole in 1.0 ml of 1-methyl-pyrrolidin-2-one
was treated at RT with 0.058 g (1.32 mmol) of a sodium hydride (55%
in mineral oil). After 30 min, 0.20 g (0.44 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was added and the
reaction mixture was heated up to 150.degree. C. After 24 hours, it
was poured into crashed ice and extracted twice with EtOAc; the
organic phases were washed with water, dried over magnesium
sulfate, filtered and evaporated. The residue was purified by flash
column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0 to 95:5) to give
0.11 g (48%) of the title compound as yellow oil. MS: 519.3
(MH.sup.+, 1Cl).
Example 21
[3,6-Dichloro-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-y-
l-piperidin-1-yl)-methanone
##STR00060##
[0269] In analogy to the procedure described for the preparation of
example 1,
3,6-dichloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid [prepared from
3,6-dichloro-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester (intermediate 11) by saponification in analogy to
the procedure described for intermediate 1B] was reacted with
4-pyrrolidin-1-yl-piperidine to give the title compound as light
yellow amorphous solid. MS: 472.1 (MH.sup.+, 2Cl).
Example 22
[3-Chloro-6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone
##STR00061##
[0271] In analogy to the procedure described for the preparation of
example 8,
[3,6-dichloro-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1--
yl-piperidin-1-yl)-methanone (example 21) was reacted with sodium
methoxide in methanol at 50.degree. C. to give the title compound
as light yellow oil. MS: 468.3 (MH.sup.+, 1Cl).
Example 23
[3-Chloro-6-hydroxy-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone;
5-Chloro-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-1H-pyridin-2-one (tautomers)
##STR00062##
[0273] In analogy to the procedure described for the preparation of
intermediate 10C,
[3-chloro-6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone (example 22) was reacted with
boron tribromide in CH.sub.2Cl.sub.2 at RT to give the title
compound as off-white solid. MS: 454.3 (MH.sup.+, 1Cl).
Example 24
[6-Ethynyl-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone
##STR00063##
[0275] A solution of 0.65 g (1.27 mmol) of
[3-methyl-5-(3-trifluoromethyl-phenyl)-6-trimethylsilanylethynyl-pyridin--
2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate
12) in 12 ml of EtOH/THF (5:1) was treated at RT with 0.35 g (2.53
mmol) of potassium carbonate. After 4 hours, the reaction mixture
was poured into crashed ice, the pH was adjusted to 3-4 with
hydrochloric acid (2 molar) and the mixture was extracted three
times with CH.sub.2Cl.sub.2; the organic phases were washed with
water, dried over magnesium sulfate, filtered and evaporated. The
residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH 1:0 to 9:1) to give 0.439 g (79%) of the
title compound as brown solid. MS: 442.3 (MH.sup.+).
Example 25
[3-Methyl-6-[1,2,4]triazol-1-yl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-
-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00064##
[0277] In analogy to the procedure described for the preparation of
example 20,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
1H-[1,2,4]triazole and sodium hydride in 1-methyl-pyrrolidin-2-one
at reflux to give the title compound as colorless solid. MS: 485.3
(MH.sup.+).
Example 26
[6-(2-Amino-ethylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl-
]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00065##
[0279] In analogy to the procedure described for the preparation of
example 6,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
ethane-1,2-diamine,
[rac]-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, palladium(II)
acetate and cesium carbonate in toluene at reflux to give the title
compound as light yellow solid. MS: 476.3 (MH.sup.+).
Example 27
[6-(2-Hydroxy-ethylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2--
yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00066##
[0281] A solution of 0.14 g (0.25 mmol) of
[6-(2-benzyloxy-ethylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-
-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate
14) in 6.0 ml of MeOH was treated at RT with 0.49 ml (0.49 mmol) of
hydrochloric acid (1.0 molar in MeOH), followed by 0.026 g (0.025
mmol) of Pd--C (10%). The reaction mixture was vigorously stirred
in an atmosphere of hydrogen for 3 hours. After filtration through
dicalite, the solvent was removed by evaporation, then the residue
was dissolved in H.sub.2O/Na.sub.2CO.sub.3 and extracted twice with
CH.sub.2Cl.sub.2; the organic phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0
to 95:5) to give 0.091 g (77%) of the title compound as yellow
amorphous solid. MS: 477.3 (MH.sup.+).
Example 28
[5-(3,4-Dichloro-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperid-
in-1-yl)-methanone
##STR00067##
[0283] In analogy to the procedure described for the preparation of
intermediate 1A,
(5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methan-
one (prepared from 5-bromo-3-methyl-pyridine-2-carboxylic acid
methyl ester [Wu, G. G.; Wong, Y.-S.; Poirier, M. Organic Letters
(1999), 1(5), 745-747], 4-pyrrolidin-1-yl-piperidine, Et.sub.3N and
HATU in DMF in analogy to the procedure described for the
preparation of example 1) was reacted with
3,4-dichlorophenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water to give the title compound as off-white amorphous
solid. MS: 418.1 (MH.sup.-, 2Cl).
Example 29
[3-Methyl-5-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-pi-
peridin-1-yl)-methanone
##STR00068##
[0285] In analogy to the procedure described for the preparation of
intermediate 1A,
(5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methan-
one (see example 28) was reacted with
2-trifluoromethyl-phenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water to give the title compound as off-white amorphous
solid. MS: 418.2 (MH.sup.+).
Example 30
[5-(2-Chloro-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone
##STR00069##
[0287] In analogy to the procedure described for the preparation of
intermediate 1A,
(5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methan-
one (see example 28) was reacted with
2-chloro-5-trifluoromethyl-phenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water to give the title compound as light brown amorphous
solid. MS: 452.2 (MH.sup.+, 1Cl).
Example 31
[5-(2-Fluoro-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone
##STR00070##
[0289] In analogy to the procedure described for the preparation of
intermediate 1A,
(5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methan-
one (see example 28) was reacted with
2-fluoro-5-trifluoromethyl-phenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water to give the title compound as brown amorphous solid.
MS: 436.3 (MH.sup.+).
Example 32
[3-Methyl-6-(1H-[1,2,3]triazol-4-yl)-5-(3-trifluoromethyl-phenyl)-pyridin--
2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00071##
[0291] 0.30 g (0.50 mmol) of
[6-[1-(4-methoxy-benzyl)-1H-[1,2,3]triazol-4-yl]-3-methyl-5-(3-trifluorom-
ethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
(intermediate 13) in 3.2 ml of trifluoroacetic acid were stirred at
reflux for 23 hours. The reaction mixture was then poured into
crashed ice, the pH was adjusted to 8-9 with aqueous
Na.sub.2CO.sub.3 and the mixture was extracted twice with
CH.sub.2Cl.sub.2; the organic phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 98:2
to 4:1) to give 0.19 g (77%) of the title compound as an off-white
solid. MS: 485.4 (MH.sup.+).
Example 33
[5-(2-Methoxy-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone
##STR00072##
[0293] In analogy to the procedure described for the preparation of
intermediate 1A,
(5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methan-
one (see example 28) was reacted with
2-methoxy-5-trifluoromethyl-phenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water to give the title compound as brown amorphous solid.
MS: 448.1 (MH.sup.+).
Example 34
[5-(4-Fluoro-3-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone
##STR00073##
[0295] In analogy to the procedure described for the preparation of
intermediate 1A,
(5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methan-
one (see example 28) was reacted with
4-fluoro-3-trifluoromethyl-phenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water to give the title compound as brown amorphous solid.
MS: 436.4 (MH.sup.+).
Example 35
[5-(4-Methoxy-3-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone
##STR00074##
[0297] In analogy to the procedure described for the preparation of
intermediate 1A,
(5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methan-
one (see example 28) was reacted with
4-methoxy-3-trifluoromethyl-phenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water to give the title compound as brown amorphous solid.
MS: 448.2 (MH.sup.+).
Example 36
[5-(2-Fluoro-3-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone
##STR00075##
[0299] In analogy to the procedure described for the preparation of
intermediate 1A,
(5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methan-
one (see example 28) was reacted with
2-fluoro-3-trifluoromethyl-phenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water to give the title compound as brown amorphous solid.
MS: 436.4 (MH.sup.+).
Example 37
[5-(3-Fluoro-5-trifluoromethyl-phenyl)-3-methyl-pyridin-2-yl]-(4-pyrrolidi-
n-1-yl-piperidin-1-yl)-methanone
##STR00076##
[0301] In analogy to the procedure described for the preparation of
intermediate 1A,
(5-bromo-3-methyl-pyridin-2-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methan-
one (see example 28) was reacted with
3-fluoro-5-trifluoromethyl-phenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water to give the title compound as brown amorphous solid.
MS: 436.4 (MH.sup.+).
Example 38
[6-Hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone;
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-1H-pyridin-2-one (tautomers)
##STR00077##
[0303] Coupling: 2.5 g (8.4 mmol) of
6-hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid/3-methyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2-c-
arboxylic acid (tautomers) (intermediate 15C) were suspended in a
mixture of 37.5 ml acetonitrile and 6.25 ml DMF. 1.48 g (8.8 mmol)
carbonyl diimidazole (CDI) was added. The suspension was stirred at
RT overnight. 1.43 g (9.25 mmol) 4-(1-pyrrolidinyl)-piperidine was
added upon which a yellow suspension was obtained which quickly
changed into a colorless suspension. After 3 h at RT (IPC by HPLC),
0.586 ml triethylamine (4.2 mmol) was added. After 2 h at RT, 25 ml
water was added. Acetonitrile was removed at the rotavap during
which a yellow solution was obtained which changed to a colorless
suspension. The suspension was stirred 1 h at RT and 1 h at
0.degree. C. The suspension was filtered. The filter cake was
washed with cold water and dried under reduced pressure (50.degree.
C./10 mbar) to give 3.02 g of crude title compound as a colorless
powder.
[0304] Digestion: 15.78 g of the crude title compound were
suspended in 158 ml water. The suspension was heated to 100.degree.
C. for 20 min and slowly cooled overnight to RT. The suspension was
further cooled to 0-5.degree. C. for 1h and was filtered. The
filter cake was washed with cold water and dried under reduced
pressure (50.degree. C./10 mbar) to give 13.76 g (72%) of the title
compound as a colorless powder. MS: 434.4 (MH).
Example 39
[6-(2-Amino-pyrimidin-5-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin--
2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00078##
[0306] In analogy to the procedure described for the preparation of
intermediate 1A,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
2-aminopyrimidin-5-yl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water at 80.degree. C. to give the title compound as dark
brown oil. MS: 511.4 (MH.sup.+).
Example 40
[6'-Amino-5-methyl-3-(3-trifluoromethyl-phenyl)-[2,3']bipyridinyl-6-yl]-(4-
-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00079##
[0308] In analogy to the procedure described for the preparation of
intermediate 5C,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine
to give the title compound as off-white solid. MS: 510.4
(MH.sup.+).
Example 41
[6'-Hydroxy-5-methyl-3-(3-trifluoromethyl-phenyl)-[2,3']bipyridinyl-6-yl]--
(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00080##
[0310] In analogy to the procedure described for the preparation of
intermediate 5C,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ol to
give the title compound as yellow amorphous solid. MS: 511.2
(MH.sup.+).
Example 42
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl--
phenyl)-pyridine-2-carbonitrile
##STR00081##
[0311] Example 43
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl--
phenyl)-pyridine-2-carboxylic acid amide
##STR00082##
[0313] A well stirred suspension of 0.30 g (0.66 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) and 0.098 g (2.0
mmol) of sodium cyanide in 5.0 ml of 1-methyl-pyrrolidin-2-one was
heated for 16 hours at 150.degree. C. After cooling down to RT, the
reaction mixture was poured into crashed ice/NaCl-solution (sat. in
H.sub.2O) and extracted three times with CH.sub.2Cl.sub.2; the
organic phases were washed with water, dried over magnesium
sulfate, filtered and evaporated. The residue was purified by flash
column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0 to 4:1) to give
0.086 g (29%) of
5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carbonitrile as light yellow solid. MS: 443.4
(MH.sup.+); and 0.045 g (15%) of
5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid amide as light yellow solid.
MS: 461.4 (MH.sup.+).
Example 44
[6-(2-Methoxy-pyrimidin-5-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridi-
n-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00083##
[0315] In analogy to the procedure described for the preparation of
intermediate 5C,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
2-methoxypyrimidin-5-yl-boronic acid to give the title compound as
light brown amorphous solid. MS: 526.2 (MH.sup.+).
Example 45
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl--
phenyl)-pyridine-2-carboxylic acid methyl ester
##STR00084##
[0317] To a degassed solution of 7.00 g (15.5 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) in 180 ml of
MeOH/EtOAc 1:1 were added 0.70 g (0.86 mmol) of
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and 5.4 ml=3.92 g (38.7 mmol)
of Et.sub.3N. This reaction mixture was stirred in an autoclave and
in a carbon monoxide atmosphere at 130.degree. C./70 bar for 30
hours. Then, it was evaporated, the residue dissolved in
H.sub.2O/EtOAc and extracted twice with EtOAc; the organic phases
were washed with water, dried over magnesium sulfate, filtered and
evaporated. The residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH 1:0 to 4:1) to give 4.61 g (63%) of the
title compound as light brown foam. MS: 476.2 (MH.sup.+).
Example 46
[6-Hydroxymethyl-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-py-
rrolidin-1-yl-piperidin-1-yl)-methanone
##STR00085##
[0319] To a solution of 0.24 g (0.51 mmol) of
5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid methyl ester (example 45) in
5.0 ml of EtOH were added 0.093 g (4.27 mmol) of lithium
borohydride in three portions. The reaction mixture was stirred at
RT for 48 hours, then poured into crashed ice, the pH was reduced
to 2-3 with hydrochloric acid (25%), and the mixture subsequently
neutralized with solid NaHCO.sub.3. Then, it was extracted twice
with CH.sub.2Cl.sub.2; the organic phases were washed with water,
dried over magnesium sulfate, filtered and evaporated. The residue
was purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH
1:0 to 9:1) to give 0.097 g (43%) of the title compound as light
yellow solid. MS: 448.1 (MH.sup.+).
Example 47
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl--
phenyl)-pyridine-2-carboxylic acid
##STR00086##
[0321] To a solution of 0.315 g (0.66 mmol) of
5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid methyl ester (example 45) in 10
ml of THF/MeOH 1:1 were added 1.32 ml of lithium hydroxide (1 molar
in H.sub.2O) and the reaction mixture was stirred at RT for 28
hours. Then, the solvents were evaporated and the residue was
dissolved in H.sub.2O/CH.sub.2Cl.sub.2, neutralized with the help
of hydrochloric acid and solid NaHCO.sub.3 and then extracted four
times with CH.sub.2Cl.sub.2/2-propanol 3:1; the organic phases were
dried over magnesium sulfate, filtered and evaporated, to give
0.188 g (62%) of the title compound as off-white solid. MS: 462.3
(MH.sup.+).
Example 48
[3-Methyl-6-(1H-pyrazol-4-yl)-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(-
4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00087##
[0323] In analogy to the procedure described for the preparation of
intermediate 5C,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to
give the title compound as colorless amorphous solid. MS: 484.2
(MH.sup.+).
Example 49
[3-Methyl-6-(1H-pyrazol-3-yl)-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(-
4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00088##
[0325] In analogy to the procedure described for the preparation of
intermediate 1A,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water at 120.degree. C. to give the title compound as
colorless solid. MS: 484.2 (MH.sup.+)
Example 50
[3-Methyl-6-(1-methyl-1H-pyrazol-4-yl)-5-(3-trifluoromethyl-phenyl)-pyridi-
n-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00089##
[0327] In analogy to the procedure described for the preparation of
intermediate 5C,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole
to give the title compound as colorless solid. MS: 498.2
(MH.sup.+).
Example 51
[3-Methyl-6-pyrazin-2-yl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyr-
rolidin-1-yl-piperidin-1-yl)-methanone
##STR00090##
[0329] To a degassed solution of 0.20 g (0.44 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) in 8.0 ml of DMF was
added 0.051 g (0.044 mmol) of
tetrakis-(triphenylphosphine)-palladium and the reaction mixture
was stirred for 20 min at RT. Then, 0.49 g (1.32 mmol) of
2-tributylstannanyl-pyrazine were added and the reaction was heated
up to 100.degree. C. After 6 hours, it was cooled down to RT,
poured into crashed ice and extracted three times with EtOAc; the
organic phases were washed with water, dried over magnesium
sulfate, filtered and evaporated. The residue was purified by flash
column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0 to 9:1) to give
0.11 g (50%) of the title compound as yellow oil. MS: 496.2
(MH.sup.-).
Example 52
[6-(2-Hydroxy-pyrimidin-5-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridi-
n-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00091##
[0331] In analogy to the procedure described for the preparation of
intermediate 10C,
[6-(2-methoxy-pyrimidin-5-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyrid-
in-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 44)
was reacted with boron tribromide in dichloromethane to give the
title compound as light yellow solid. MS: 512.2 (MH.sup.+).
Example 53
[3-Methyl-6-(2-methyl-2H-pyrazol-3-yl)-5-(3-trifluoromethyl-phenyl)-pyridi-
n-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00092##
[0333] In analogy to the procedure described for the preparation of
intermediate 1A,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
5-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-1-methyl-1H-pyrazole to
give the title compound as dark brown oil. MS: 498.2
(MH.sup.+).
Example 54
[6-(2,4-Dihydroxy-pyrimidin-5-yl)-3-methyl-5-(3-trifluoromethyl-phenyl)-py-
ridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00093##
[0335] To a degassed solution of 0.20 g (0.44 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) in 10 ml of
1,2-dimethoxyethane was added 0.138 g (0.88 mmol) of
2,4-dihydroxy-pyrimidine-5-boronic acid, 0.051 g (0.044 mmol) of
tetrakis-(triphenylphosphine)-palladium and 0.031 g (0.088 mmol) of
2-(dicyclohexylphosphino)biphenyl, followed by 0.071 g (0.67 mmol)
of sodium carbonate and 3.4 ml of H.sub.2O. Finally, the reaction
mixture was warmed up to 80.degree. C. After 48 hours, it was
cooled down to RT, poured into crashed ice and extracted twice with
EtOAc; the organic phases were washed with water, dried over
magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 1:0
to 4:1) to give 0.035 g (15%) of the title compound as off-white
solid. MS: 528.2 (MH.sup.+).
Example 55
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl--
phenyl)-pyridine-2-carboxylic acid (2-hydroxy-ethyl)-amide
##STR00094##
[0337] In analogy to the procedure described for the preparation of
example 1,
5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with
ethanolamine, Et.sub.3N and HATU in DMF to give the title compound
as light yellow solid. MS: 505.2 (MH.sup.+).
Example 56
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl--
phenyl)-pyridine-2-carboxylic acid pyridin-3-ylamide
##STR00095##
[0339] In analogy to the procedure described for the preparation of
example 1,
5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with
3-aminopyridine, Et.sub.3N and HATU in DMF to give the title
compound as light yellow solid. MS: 538.2 (MH.sup.+).
Example 57
4-{[5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromet-
hyl-phenyl)-pyridine-2-carbonyl]-amino}-piperidine-1-carboxylic
acid tert-butyl ester
##STR00096##
[0341] In analogy to the procedure described for the preparation of
example 1,
5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with
4-amino-piperidine-1-carboxylic acid tert-butyl ester, Et.sub.3N
and HATU in DMF to give the title compound as light yellow solid.
MS: 644.3 (MH.sup.+).
Example 58
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl--
phenyl)-pyridine-2-carboxylic acid methylamide
##STR00097##
[0343] In analogy to the procedure described for the preparation of
example 1,
5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with
methylamine (solution in EtOH), Et.sub.3N and HATU in DMF to give
the title compound as light yellow solid. MS: 475.2 (MH.sup.+).
Example 59
4-[5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluorometh-
yl-phenyl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid
tert-butyl ester
##STR00098##
[0345] In analogy to the procedure described for the preparation of
example 1,
5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with
piperazine-1-carboxylic acid tert-butyl ester, Et.sub.3N and HATU
in DMF to give the title compound as light yellow solid. MS: 630.3
(MH.sup.+).
Example 60
5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl--
phenyl)-pyridine-2-carboxylic acid piperidin-4-ylamide
##STR00099##
[0347] A solution of 0.20 g (0.31 mmol) of
4-[5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromet-
hyl-phenyl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid
tert-butyl ester (example 59) in 10 ml of MeOH was treated with
0.39 ml (1.56 mmol) of HCl in dioxane (4 molar) and the reaction
mixture was then stirred at RT. After 18 hours, it was evaporated,
poured into crashed ice, the pH was adjusted to 8-9 with sodium
carbonate solution and the mixture was then extracted twice with
CH.sub.2Cl.sub.2; the organic phases were washed with water, dried
over magnesium sulfate, filtered and evaporated. The residue was
purified by flash column chromatography (CH.sub.2Cl.sub.2/MeOH 95:5
to 4:1) to give 0.127 g (75%) of the title compound as light yellow
solid. MS: 544.3 (MH.sup.+).
Example 61
[5-Methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-
-phenyl)-pyridin-2-yl]-piperazin-1-yl-methanone
##STR00100##
[0349] In analogy to the procedure described for the preparation of
example 60,
4-[5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromet-
hyl-phenyl)-pyridine-2-carbonyl]-piperazine-1-carboxylic acid
tert-butyl ester (example 59) was reacted with HCl/dioxane in
methanol to give the title compound as light yellow solid. MS:
530.2 (MH.sup.+).
Example 62
[3-Methyl-6-(pyridin-3-yloxy)-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(-
4-pyrrolidin-1- yl-piperidin-1-yl)-methanone
##STR00101##
[0351] In analogy to the procedure described for the preparation of
example 20,
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with
pyridin-3-ol and sodium hydride in 1-methyl-pyrrolidin-2-one at
reflux to give the title compound as colorless oil. MS: 511.4
(MH.sup.+).
Example 63
1,5-Dimethyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromet-
hyl-phenyl)-1H-pyridin-2-one
##STR00102##
[0353] In analogy to the procedure described for the preparation of
example 13,
1,3-dimethyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2-ca-
rboxylic acid [prepared by i) reaction of
6-hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester;
3-methyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2-carbox-
ylic acid methyl ester (tautomers, intermediate 15B) with methyl
iodide, cesium carbonate in DMF in analogy to the procedure
described for the preparation of intermediate 5F; ii)
saponification of the thus formed
1,3-dimethyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2-ca-
rboxylic acid methyl ester with lithium hydroxide in THF/MeOH in
analogy to the procedure described for the preparation of
intermediate 5G] was reacted with oxalyl chloride/DMF in
CH.sub.2Cl.sub.2 followed by treatment with
4-pyrrolidin-1-yl-piperidine to give the title compound as
colorless solid. MS: 448.2 (MH.sup.+).
Example 64
[6-Mercapto-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrroli-
din-1-yl-piperidin-1-yl)-methanone;
[3-Methyl-6-thioxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridin-2-yl]-
-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (tautomers)
##STR00103##
[0355] 0.45 g (1.0 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) was dissolved in 10.0
ml of DMF, then 0.18 g (2.50 mmol) of potassium hydrogen sulfide
were added and the mixture was heated up to 110.degree. C. After 2
hours, it was cooled down to RT, poured into crashed ice, the pH
was adjusted to 7-8 with AcOH (2 molar in H.sub.2O) and the mixture
was extracted twice with CH.sub.2Cl.sub.2; the organic phases were
washed with water, dried over magnesium sulfate, filtered and
evaporated. The residue was purified by flash column chromatography
(CH.sub.2Cl.sub.2/MeOH 98:2 to 95:5) to give 0.198 g (44%) of the
title compound as off-white solid. MS: 450.2 (MH.sup.+).
Example 65
[6-Methyl-8-(3-trifluoromethyl-phenyl)-tetrazolo[1,5-a]pyridin-5-yl]-(4-py-
rrolidin-1-yl-piperidin-1-yl)-methanone
##STR00104##
[0357] A solution of 0.20 g (0.44 mmol) of
[6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolid-
in-1-yl-piperidin-1-yl)-methanone (example 3) in 2.0 ml of DMF was
treated with 0.099 g (1.52 mmol) of a sodium azide and the reaction
mixture was heated up to 150.degree. C. After 48 hours, it was
poured into crashed ice and extracted twice with EtOAc; the organic
phases were washed with water, dried over magnesium sulfate,
filtered and evaporated. The residue was purified by flash column
chromatography (CH.sub.2Cl.sub.2/MeOH 98:2 to 4:1) to give 0.095 g
(47%) of the title compound as colorless oil. MS: 459.4
(MH.sup.-).
Example 66
[6-(2-Hydroxy-ethoxy)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]--
(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone
##STR00105##
[0359] In analogy to the procedure described for the preparation of
example 27,
[6-(2-benzyloxy-ethoxy)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-y-
l]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone [prepared by i)
reaction of
6-hydroxy-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic
acid methyl ester;
3-methyl-6-oxo-5-(3-trifluoromethyl-phenyl)-1,6-dihydro-pyridine-2-carbox-
ylic acid methyl ester (tautomers, intermediate 15B) with
benzyl-2-bromoethyl ether, cesium carbonate, potassium iodide in
DMSO in analogy to the procedure described for the preparation of
intermediate 5F; ii) saponification of the thus formed
6-(2-benzyloxy-ethoxy)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-c-
arboxylic acid methyl ester with lithium hydroxide in THF/MeOH in
analogy to the procedure described for the preparation of
intermediate 5G; iii) reaction of the thus formed
6-(2-benzyloxy-ethoxy)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridine-2-c-
arboxylic acid with oxalyl chloride/DMF in CH.sub.2Cl.sub.2
followed by treatment with 4-pyrrolidin-1-yl-piperidine in analogy
to the procedure described for the preparation of example 13] was
treated with hydrogen, Pd--C, in MeOH/HCl to give the title
compound as colorless oil. MS: 478.2 (MH.sup.+).
Example 67
[5-(2-Fluoro-5-trifluoromethyl-phenyl)-3-methyl-1-oxy-pyridin-2-yl]-(4-pyr-
rolidin-1-yl-piperidin-1-yl)-methanone
##STR00106##
[0361] In analogy to the procedure described for the preparation of
example 1,
5-(2-fluoro-5-trifluoromethyl-phenyl)-3-methyl-1-oxy-pyridine-2-carboxyli-
c acid [prepared by i) reaction of
5-bromo-3-methyl-pyridine-2-carboxylic acid methyl ester with
2-fluoro-5-trifluoromethyl-phenyl-boronic acid,
(1,1'-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride
(1:1 complex with CH.sub.2Cl.sub.2) and sodium carbonate in
dioxane/water in analogy to the procedure described for the
preparation of intermediate 1A; ii) oxidation of the thus formed
5-(2-fluoro-5-trifluoromethyl-phenyl)-3-methyl-pyridine-2-carboxylic
acid methyl ester with 3-chloro-perbenzoic acid in dichloromethane
in analogy to the procedure described for the preparation of
intermediate 1C; iii) saponification of the thus formed
5-(2-fluoro-5-trifluoromethyl-phenyl)-3-methyl-1-oxy-pyridine-2-carboxyli-
c acid methyl ester with lithium hydroxide in THF/MeOH in analogy
to the procedure described for the preparation of intermediate 5G]
was reacted with 4-pyrrolidin-1-yl-piperidine, Et.sub.3N and HATU
in DMF to give the title compound as light yellow amorphous solid.
MS: 452.2 (MH.sup.+).
Example A
[0362] Film coated tablets containing the following ingredients can
be manufactured in a conventional manner:
TABLE-US-00002 Ingredients Per tablet Kernel: Compound of formula
(I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg Povidone K30 12.5 mg 15.0 mg Sodium
starch glycolate 12.5 mg 17.0 mg Magnesium stearate 1.5 mg 4.5 mg
(Kernel Weight) 120.0 mg 350.0 mg Film Coat: Hydroxypropyl methyl
cellulose 3.5 mg 7.0 mg Polyethylene glycol 6000 0.8 mg 1.6 mg Talc
1.3 mg 2.6 mg Iron oxyde (yellow) 0.8 mg 1.6 mg Titan dioxide 0.8
mg 1.6 mg
[0363] The active ingredient is sieved and mixed with
microcristalline cellulose and the mixture is granulated with a
solution of polyvinylpyrrolidone in water. The granulate is mixed
with sodium starch glycolate and magnesiumstearate and compressed
to yield kernels of 120 or 350 mg respectively. The kernels are
lacquered with an aqueous solution/suspension of the above
mentioned film coat.
Example B
[0364] Capsules containing the following ingredients can be
manufactured in a conventional manner:
TABLE-US-00003 Ingredients Per capsule Compound of formula (I) 25.0
mg Lactose 150.0 mg Maize starch 20.0 mg Talc 5.0 mg
[0365] The components are sieved and mixed and filled into capsules
of size 2.
Example C
[0366] Injection solutions can have the following composition:
TABLE-US-00004 Compound of formula (I) 3.0 mg Polyethylene Glycol
400 150.0 mg Acetic Acid q.s. ad pH 5.0 Water for injection
solutions Ad 1.0 ml
[0367] The active ingredient is dissolved in a mixture of
Polyethylene Glycol 400 and water for injection (part). The pH is
adjusted to 5.0 by Acetic Acid. The volume is adjusted to 1.0 ml by
addition of the residual amount of water. The solution is filtered,
filled into vials using an appropriate overage and sterilized.
Example D
[0368] Soft gelatin capsules containing the following ingredients
can be manufactured in a conventional manner:
TABLE-US-00005 Capsule contents Compound of formula (I) 5.0 mg
Yellow wax 8.0 mg Hydrogenated Soya bean oil 8.0 mg Partially
hydrogenated plant oils 34.0 mg Soya bean oil 110.0 mg Weight of
capsule contents 165.0 mg Gelatin capsule Gelatin 75.0 mg Glycerol
85% 32.0 mg Karion 83 8.0 mg (dry matter) Titan dioxide 0.4 mg Iron
oxide yellow 1.1 mg
[0369] The active ingredient is dissolved in a warm melting of the
other ingredients and the mixture is filled into soft gelatin
capsules of appropriate size. The filled soft gelatin capsules are
treated according to the usual procedures.
Example E
[0370] Sachets containing the following ingredients can be
manufactured in a conventional manner:
TABLE-US-00006 Compound of formula (I) 50.0 mg Lactose, fine powder
1015.0 mg Microcristalline cellulose (AVICEL PH 102) 1400.0 mg
Sodium carboxymethyl cellulose 14.0 mg Polyvinylpyrrolidon K 30
10.0 mg Magnesiumstearate 10.0 mg Flavoring additives 1.0 mg
[0371] The active ingredient is mixed with lactose,
microcristalline cellulose and sodium carboxymethyl cellulose and
granulated with a mixture of polyvinylpyrrolidon in water. The
granulate is mixed with magnesiumstearate and the flavouring
additives and filled into sachets.
[0372] Unless stated to the contrary, all compounds in the examples
were prepared and characterized as described. All ranges recited
herein encompass all combinations and subcombinations included
within that range limit. All patents and publications cited herein
are hereby incorporated by reference in their entirety.
* * * * *